RxPG News : Blood

Investigational drug, RI-BPI, in combination with the drug Gleevec, effective against acute lymphoblastic leukemia

Tue, 24 May 2011 17:25:05 PST

( from http://www.rxpgnews.com ) In a significant breakthrough, investigators at Weill Cornell Medical College and the University of California, San Francisco, have been able to overcome resistance of a form of leukemia to targeted therapy, demonstrating complete eradication of the cancer in cell and animal studies.

Their study, published in the May 19 issue of Nature, shows that an investigational drug, RI-BPI, developed at Weill Cornell, in combination with the drug Gleevec shut down stem cells responsible for about one-third of acute lymphoblastic leukemia (ALL), a cancer of white blood cells that affects young children as well as older adults.

This form of ALL has the so-called Philadelphia chromosome, which is also found in chronic myelogenous leukemia (CML). But while Gleevec has greatly improved survival in CML, it has had a less dramatic effect in ALL, and most patients still die within a relatively short timeframe.

That desperate prognosis may radically change given these results, says co-senior investigator Dr. Ari Melnick, associate professor of medicine and director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College, and a hematologist-oncologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

"I am surprised, and extremely glad, to see that RI-BPI has such strong activity in a leukemia. This opens up the possibility that the agent will have similar beneficial effects in other tumor types," says Dr. Melnick.

Dr. Melnick and his colleagues developed RI-BPI and they have shown its potent effects in non-Hodgkin's lymphoma (NHL) with no toxicity to normal cells. The drug targets the transcription factor BCL6, a master regulator of hundreds of genes that provides strong growth signals to NHL cells.

The new study demonstrated that BCL6 is also active in ALL driven by the Philadelphia chromosome (Ph+ ALL), and that a combination of RI-BPI and Gleevec virtually shuts the cancer down, says Dr. Melnick. After a long search for the source of Gleevec resistance in this form of ALL by the team at the University of California, San Francisco (UCSF), it appears that BCL6 is the fundamental mediator of that resistance, he explains. "This gives us an opportunity to target Gleevec resistance, something that has the potential to substantially improve outcomes for patients with this disease."

The UCSF research team discovered that production of BCL6 is turned on after administration of Gleevec in Ph+ ALL. UCSF investigators then initiated collaborative research with Dr. Melnick, who provided RI-BPI and conducted experiments on how BCL6 regulates genes in leukemia cells.

The UCSF team also conducted animal tests and discovered that BCL6 hits the stem cells that give rise to ALL. "These stem cells continually repopulate disease cells by making copies of themselves," Dr. Melnick says. "We believe RI-BPI counteracts the BCL6 gene regulatory program that these stem cells need to survive.

"BCL6 turns off the brakes that normally limit cancer growth, which is why Gleevec does not work in this cancer, but RI-BPI puts those brakes back on," he says.

The study also suggests that transcription factors like BCL6 may be less impervious than once thought to targeted treatment, Dr. Melnick says. BCL6 is a protein, and it "mediates its cancer-causing actions by attaching to other proteins. Traditionally, however, protein-protein interactions have been viewed as being too difficult to block with small-molecule drugs."

Although it has yet to be tested in refractory CML -- CML that has become resistant to Gleevec, which occurs in most patients over time -- it makes sense that RI-BPI could restore Gleevec sensitivity, Dr. Melnick adds.

"From this study and from the others in my lab, I have become very impressed with how reliant tumor cells are on certain proteins for their survival," he says. "If we can hit several of these brittle and dependent processes, we have the chance to eradicate cancer."

Based on this study, a clinical trial is being developed to treat children with Ph+ ALL with a combination of RI-BPI.

Reprogramming of diseased cells back into pluripotent stem cells provides model for studying the stages of cancer development

Sun, 06 Feb 2011 17:02:57 PST

( from http://www.rxpgnews.com ) By reprogramming of diseased human bone marrow to become embryonic-like stem cells, a team of Wisconsin scientists has laid the groundwork for observing the onset of the blood cancer leukemia in the laboratory dish.

"This is the first successful reprogramming of blood cells obtained from a patient with leukemia," says University of Wisconsin-Madison stem cell researcher Igor Slukvin, who directed a study aimed at generating all-purpose stem cells from bone marrow and umbilical cord blood. "We were able to turn the diseased cells back into pluripotent stem cells. This is important because it provides a new model for the study of cancer cells."

The research was reported in the journal Blood (Feb 4) by Slukvin and colleagues from the WiCell Research Institute and the Morgridge Institute for Research, private research centers in Madison.

Slukvin's group, using banked healthy and diseased bone marrow and cord blood, employed a technique developed in 2009 by Wisconsin stem cell pioneer James Thomson that sidesteps the problems posed by the genes and viral vectors used to induce mature cells to regress to a stem cell state.

According to the new study, which was funded by the National Institutes of Health and The Charlotte Geyer Foundation, reprogramming blood cells to become induced stem cells is many times more efficient than the reprogramming of skin cells, which were the first mature cells to be guided back to an embryonic stem cell-like state.

The new work could open to science vast repositories of banked tissue, both healthy and diseased, such as bone marrow, the soft tissue in bones that helps make blood, and umbilical cord blood. The work could underpin insightful models capable of unmasking the cellular events that go awry and cause cancers such as leukemia, and could aid the development of new stem cell-based therapies, according to Slukvin.

Of particular note in the new study, says Slukvin, is the reprogramming of marrow cells from a patient with chronic myeloid leukemia, a cancer of the blood that kills about 1,500 people a year in the United States. The disease, like all leukemias, starts in the cells that produce white blood cells in bone marrow.

According to Slukvin, the induced stem cells generated from the diseased tissue retain the exact same complex of genetic abnormalities found in the mature cancer cells. That means that when the induced cells are turned back into blood, scientists could, in theory, watch cancer develop from scratch as cells bearing cancer mutations become cancer stem cells.

"When we differentiate induced stem cells back to blood, we can identify the stages when the abnormality that leads to cancer manifests itself," Slukvin explains.

The ability to pinpoint the very earliest stages of cancer is a major focus of biomedical science.

"This is very important for developing new leukemia drugs," says Slukvin. "A major focus of leukemia research is to find ways to try and eliminate the most immature leukemia cells - cancer stem cells."

The work by Slukvin and his team may represent the first step in a new understanding of the cascade of events that results in blood diseases such as leukemia.

Employing the reprogramming technique developed by Thomson and his colleagues, Slukvin emphasizes, is important because it eliminates the exotic reprogramming genes, some of which are cancer-related genes, from the induced stem cell equation. In the case of chronic myeloid leukemia and other blood diseases, obtaining stem cells that do not have the genetic reprogramming factors is very important.

"When you use viruses (to ferry genes into a cell) you have chromosomal integration," the Wisconsin researcher notes. "Some of the reprogramming factors are oncogenes and would interfere with a study of chronic myeloid leukemia" whose abnormalities are also encoded on the chromosome.

Discovery that can lead to new drugs for Leukaemia

Sun, 20 Jan 2008 09:50:16 PST

( from http://www.rxpgnews.com ) Researchers at the University of East Anglia have discovered for the first time a pathway that makes cancerous leukaemia cells resistant to treatment.

The scientists found that death-resistant Acute Myeloid Leukaemia cells are given their resistance by a genetic anti-oxidant pathway called hemeoxygenase-1 or HO-1. This resistance pathway leads to relapse of the disease and non-responsiveness to treatments. When this pathway is inhibited, the cells lose their resistance and become responsive to death-inducing agents.

Published online in the journal Blood on Friday January 18, the discovery is the first stage in the development of new drugs that could significantly improve survival rates for leukaemia sufferers.

“This is a major step forward in the treatment of leukaemia and other cancers,” said Prof David MacEwan who led the research team.

“The next step will be a programme to develop a new set of targeted therapies to treat not only Acute Myeloid Leukaemia, but other leukaemias and other cancers.”

Leukaemia is one of the six biggest cancer killers in the UK and more people die of Acute Myeloid Leukaemia (AML) than any other form of leukaemia. AML attacks the white blood cells and is a common form in both children and adults with leukaemia. It is currently treated by a range of chemotherapy drugs. Many patients go on to have bone marrow transplants due to commonly developing drug-resistance to their initial chemotherapy.

The antioxidant response element (ARE) genes which include HO-1, protect cells from damage and their killing off by cytotoxic agents such as chemotherapy drugs. The team found that drug-resistant leukaemia cells have overactive ARE genes that cause them to be completely resistant to cytotoxic drugs, and that blocking this pathway reverts the cells into responding normally to cytotoxic agents.

Screening for p53 would predict sensitivity to proteasome inhibitors

Sat, 10 Mar 2007 11:40:03 PST

( from http://www.rxpgnews.com )

Green staining depicts tumor cells dying after treatment with proteasome inhibitors. Here, the tumor lacks p53, and only a fraction of the cells are killed.

Researchers at the University of Pennsylvania Schools of Medicine and Veterinary Medicine have determined a way to pre-screen cancer patients to see if they are suitable candidates for proteasome inhibitors, a promising class of anti-cancer drugs. They propose to test for p53, a well-known tumor-suppressor protein that is broken down by cellular machinery called proteasomes. This study appears online in the journal Blood, in advance of print publication in June 2007.

In cancer patients whose tumors do not produce p53, proteasome inhibitors might be ineffective. This patient group could be spared unnecessary treatment with possible harmful side effects. On the other hand, proteasome inhibitors are highly effective against lymphomas that do have the ability to produce p53.

Proteasomes resemble paper shredders they break down proteins such as p53 into smaller pieces, says senior author Andrei Thomas-Tikhonenko, PhD, Associate Professor of Pathology. A proteosome inhibitor effectively jams the shredder so that p53 is not immediately broken down.

In this study, the research team used a mutant strain of mice in which p53 activity can be switched on and off. In principle, tumors in these mice could be obliterated by turning p53 back on, says Thomas-Tikhonenko. The problem was that a protein called MDM2 sent p53 into the teeth of the proteasome shredder. The proteasome inhibitor bortezomib (Velcade®) causes this jamming process and restores p53 function. However, if p53 was inactivated in the mice, bortezomib treatment failed to kill tumors. Similar effects were seen with cell lines derived from human Burkitts lymphomas. When implanted into mice, these lymphoma cells were highly sensitive to the proteasome inhibitor, but as soon as p53 was removed, the inhibitor had no effect.

These findings have important implications for clinical practice, Thomas-Tikhonenko adds. Bortezomib is approved by the Food and Drug Administration for the treatment of multiple myeloma, another cancer of lymphoid cells. Yet, only a fraction of multiple myeloma patients respond to the drug.

The researchers speculate that responsive myelomas are the ones retaining the p53 protein, which gets stabilized during treatment and triggers self-destruction of cancerous cells. If confirmed experimentally, our hypothesis will serve to pre-select patients with the best chances of success those with p53 and spare the rest those without p53 the severe side effects of bortezomib therapy, explains Thomas-Tikhonenko.

There are two ways, suggest the researchers, to test for p53 production in cancer patients. First, if MDM2 is expressed at abnormally high levels, it is a good indicator that p53 is constantly being made. Second, genetic tests can also be conducted to see if the malignant cells still have the gene for p53 or if the portion of the chromosome on which p53 is found has been deleted.

In addition to Thomas-Tikhonenko, Duonan Yu and Martin Carroll, both from Penn, were co-authors. The National Institutes of Health and the Commonwealth of Pennsylvania Health Research Formula Fund provided funding for this research.

Oblimersen enhances sensitivity to chemotherapy in Chronic Lymphocytic Leukemia

Thu, 15 Feb 2007 03:36:18 PST

( from http://www.rxpgnews.com ) The first "antisense" drug to be tested in chronic lymphocytic leukemia (CLL) shows benefit in a phase III clinical trial for a specific subset of patients - those who are still sensitive to a chemotherapy drug often used to treat this cancer.

Researchers at The University of Texas M. D. Anderson Cancer Center, reporting in the early on-line edition of the March 20 Journal of Clinical Oncology, found that the agent, oblimersen (trade name: Genasense) produced a four-fold increase in "CP/nPR," a clinical response defined by no definitive evidence of disease, in patients who were sensitive to the chemotherapy drug fludarabine, compared to patients who no longer responded to fludarabine.

"The results make sense because oblimersen is designed to work alongside chemotherapy," says the study's lead author, Susan O'Brien, M.D., professor in the Department of Leukemia. "We found in this study that oblimersen enhances sensitivity to chemotherapy, and so we think it deserves further study in a population of CLL patients who are sensitive to chemotherapy agents," she says.

CLL, a cancer of the blood and bone marrow, is the second most common type of leukemia in adults. More than 15,000 new cases of the disease will be diagnosed this year, according to the American Cancer Society, and about 4,500 people will die from the cancer.

Fludarabine is a newer chemotherapy drug that is now being used as first treatment for many patients, according to O'Brien. Oblimersen is an experimental agent that inhibits the production of a protein known as Bcl-2 in cancer cells. This protein can stop a cell from destroying itself, and is often over-expressed in cancer. As an antisense drug, oblimersen provides a complementary genetic strand to the messenger RNA that produces Bcl-2, inactivating it and preventing the protein from being produced. "It gets rid of Bcl-2, and cells that have less Bcl-2 are more sensitive to chemotherapy," O'Brien says.

This study focused on patients who had relapsed after a prior fludarabine - containing regimen or were refractory to fludarabine; refractory patients had failed to respond to a prior fludarabine-based regimen or had progressed within six months of treatment. It enrolled 241 patients at cancer centers worldwide who were randomized to receive fludarabine combined with cyclophosphamide chemotherapy or the same regimen combined with oblimersen.

Researchers found that the primary endpoint of the study (CR/nPR) was achieved in 20 of the 120 patients (17 percent) in the oblimersen-treated group compared to 8 of 121 patients (7 percent) in the group treated with chemotherapy alone. This difference was statistically significant, says O'Brien.

Patients achieving nPR met all the criteria associated with a complete remission, except that on a bone marrow biopsy a nodule could be detected, which might or might not, be cancerous, she says. They did not experience the fever, night sweats, fatigue, abdominal discomfort or other symptoms associated with the disease for at least 180 days.

Although overall response rate was not significantly different between the two groups, maximum benefit was observed in fludarabine-sensitive patients, O'Brien says. This group included 51 patients in the oblimersen group and 50 patients in the group treated with chemotherapy alone, according to researchers.

For example, among all patients, median survival at 36 months was about the same - an estimated 33.8 months in the oblimersen-treated group and 32.9 months in patients treated with chemotherapy. But in patients who achieved CR/nPR, survival was three or more years in 70 percent of the patients in the oblimersen group compared with 38 percent in the chemotherapy-alone group, the researchers found. "Patients who were previously refractory to fludarabine did not benefit substantially from the addition of oblimersen, and because there were so many refractory patients in both arms of the trial, the survival curves were not significantly different between the groups," O'Brien says.

"We aimed to increase the CR/nPR rate to chemotherapy, and that aim was met," O'Brien says. "For CLL patients whose disease has progressed, but who are still sensitive to chemotherapy, oblimersen may represent a new treatment option."

Led by M. D. Anderson, collaborators in the study included investigators in the United States, Canada, Poland, Argentina and Australia.

African-Americans receive fewer stem cell transplants than whites

Thu, 08 Feb 2007 02:56:43 PST

( from http://www.rxpgnews.com ) Lower transplant rates in ethnic communities may be explained somewhat by a lack of suitable anonymous donors, a problem the medical community has long known and been working to address. Surprisingly, the study found the discrepancy in treatment held true even when the transplant was autologous (e.g. self-donated stem cells were used) or when the cells were donated by a relative, typically a sibling.

"The National Marrow Donor Program has made great strides in increasing the number of African-American donors, which is important because non-related donors are more likely to have a tissue type that matches the patient if they are of the same ethnic group," said Mary Horowitz, M.D., M.S., chief scientific director for the Center for International Blood and Marrow Transplant Research (CIBMTR) and professor of medicine at the Medical College of Wisconsin, Milwaukee. "But our research shows the problem is more extensive than we thought, and if all we do is increase the number of available anonymous donors, we won't be successful in making sure that everyone who needs transplant gets one. While the shortage of appropriate anonymous donors is an understandable cause of a lower rate of unrelated donor transplantation, it should not affect the use of autologous or related donor transplants in African-Americans, yet the rates of these transplants are also lower."

Stem cell transplant (also known as blood and marrow transplant) is used to treat diseases of the blood and several types of cancer. In the study, researchers looked at the rate of stem cell transplants among African-Americans, Caucasians and men and women for the treatment of three types of cancer most commonly treated with stem cell transplants: leukemia, lymphoma and multiple myeloma. Together, these cancers account for nearly 10 percent of all cancer cases in the United States.

Patients who are candidates for stem cell transplants are most likely to find a matching donor in someone of their own ethnicity. The group of genes known as human leukocyte antigens (HLA) in the donor and patient must be closely matched for the procedure to be successful, and that is more likely to be true within ethnic groups. Because African-Americans have a greater variation of HLA types, it is estimated that three times as many African-American donors are needed to equal the chance of obtaining a Caucasian match, according to the National Cord Blood Program.

The next step is for researchers to determine why the stem cell transplant self-donation and relative-donation rates differ between Caucasians and African-Americans. Among the potential reasons:

Differences in insurance coverage for sophisticated or aggressive health care treatments, including stem cell transplants

The effect of cultural attitudes toward the medical system
Physicians attitudes toward minorities

Bias among doctors and patients; for instance, doctors may make assumptions about how different communities feel about aggressive therapy, including stem cell transplants

"The National Marrow Donor Program and the Center for International Blood and Marrow Transplant Research are interested in exploring the reasons for the discrepancy, and may conduct focus groups regarding barriers to participation in transplantation among minorities," said J. Douglas Rizzo, M.D. M.S., associate scientific director of CIBMTR and associate professor of medicine at the Medical College of Wisconsin.

The study also looked at gender differences and although men were somewhat more likely than women to receive autologous stem-cell transplants, the difference wasn't striking and may be just a statistical anomaly, said Dr. Horowitz.

Previous studies have shown that African-Americans are more likely to be diagnosed at advanced stages of cancer and less likely to receive optimal care than Caucasians.

Stem cells are progenitor cells in the bone marrow and blood stream, meaning they can develop into a number of different cell types. Stem cells can be damaged by disease, such as cancer, or treatment, such as chemotherapy or radiation. Stem cell transplant involves taking the cells from healthy donors and infusing them in the ill patient, where they can reproduce more healthy stem cells and strengthen the patient's immune system. Stem cells may be collected, or harvested, directly from the bone marrow, or from the circulating blood and infused into the patient's bloodstream. In addition to being donated anonymously or by a relative, stem cells can sometimes be self-donated. That is, they are removed from the patient, conditioned, and reinfused in the patient after chemotherapy or other stem cell-destroying treatment.

Predicting response of treatment in Multiple Myeloma patients

Sun, 10 Dec 2006 12:50:40 PST

( from http://www.rxpgnews.com ) Researchers at Mayo Clinic Cancer Center, in cooperation with industry partners, have, for the first time, identified tumor specific alterations in the cellular pathway by which the multiple myeloma drug bortezomib (Velcade) works, and they have identified nine new genetic mutations in cancer cells that should increase a patient's chance of responding to the agent.

The investigators say these findings, presented Sunday, Dec. 10, at the 2006 American Society of Hematology Annual Meeting in Orlando, may help physicians tailor treatment to patients with multiple myleoma, a difficult-to-treat cancer of plasma cells that is the second most common blood cancer in the United States.

"Bortezomib seems to work in about one-third of patients who use it, but we have not been able to predict which ones," says the study's lead author, Leif Bergsagel, M.D., a hematologist at Mayo Clinic Arizona. "We now have identified a group that will likely respond because these nine mutations seem to be present in at least 25 percent of newly diagnosed patients.

"Now that we know the pathway the drug targets, and genetic mutations within this pathway that make patients respond better, we are working on a simple way to select those patients who are the best candidates for use of bortezomib," says Dr. Bergsagel.

In 2003, after only a four-month review, the Food and Drug Administration (FDA) approved use of bortezomib in patients who have failed other treatments for multiple myeloma. Later studies showed it lengthened survival by as much as six months. The drug was the first approved in a new class of agents known as proteasome inhibitors. Proteasomes are large protein groups inside cells that break down other proteins. Agents that inhibit the proteasome cause a buildup of proteins that affect many signaling cascades (various necessary biological processes). Bortezomib was initially thought to exert its activity by disrupting one of two known NF-êB (Nuclear Factor kappa B) pathways which keep cancer cells from self destructing the first-discovered, or canonical, NF-êB pathway.

But through extensive genetic examination of 42 unique multiple myeloma cell lines and tumor samples taken from 68 patients, the investigators defined multiple genetic mutations in the other NF-êB pathway, the so-called non-canonical pathway. "These mutations make the tumor more dependent on that pathway, and consequently more susceptible to bortezomib treatment," said senior author Rafael Fonseca, M.D., also at Mayo Clinic in Arizona.

"Identifying these mutations in patients will help us decide who should be treated with bortezomib, probably as an initial therapy," he says. The researchers are developing a test to check for activation of the non-canonical NF-êB pathway in patients.

Now that the mutations have been identified, drug designers may be able to fashion new therapies that are more specific to these genetic alterations and, therefore, less toxic,

Dr. Bergsagel says. "These mutations represent good targets for drug development," he says.

Lenalidomide effective in chronic lymphocytic leukemia

Mon, 04 Dec 2006 11:19:06 PST

( from http://www.rxpgnews.com ) Patients treated with lenalidomide for relapsed chronic lymphocytic leukemia (CLL) or disease that no longer responds to chemotherapy have experienced a major response to therapy, according to a phase II study conducted by Asher Chanan-Khan, MD, Department of Medicine, Roswell Park Cancer Institute (RPCI).

"Chronic lymphocytic leukemia is the most common hematologic malignancy in the western hemisphere," according to Dr. Chanan-Khan, "and remains incurable." While several phase II studies have demonstrated improved clinical response to chemotherapy alone, or combined with the monoclonal antibody rituximab, relapse is inevitable and treatment options at that point are limited.

Lenalidomide is a novel immune modulating, non-chemotherapy, cancer drug that is chemically similar to thalidomide, but is more potent in the laboratory and appears to lack some of the more common side effects of thalidomide. Anticancer activity of this agent has been reported in various malignant disorders, including multiple myeloma and myelodysplastic syndrome.

In this phase II study – the first to report clinical activity of lenalidomide in patients with CLL – 45 patients with immunophenotypically diagnosed B-CLL were treated with a daily dose of 25 mg of lenalidomide. Major clinical responses were seen in 21 (47%) of the patients, with four achieving complete response and 17 achieving a partial response; all with a predictable and manageable safety profile. The most common side effects included fatigue, neutropenia and thrombocytopenia.

"Collectively, these data provide strong support for further pursuit of lenalidomide in confirmatory clinical studies that are now open at Roswell Park and other cancer centers in the country," notes Dr. Chanan-Khan.

Medication errors affect children's leukemia treatment

Mon, 14 Aug 2006 11:34:00 PST

( from http://www.rxpgnews.com ) Almost one in five children treated for acute lymphoblastic leukemia (ALL) does not receive the appropriate chemotherapy regimen due to medication errors, according to a new study. Published in the September 15, 2006 issue of CANCER, a peer-reviewed journal of the American Cancer Society, the study reveals that 10 percent of chemotherapeutic medications for outpatients were prescribed or administered incorrectly. Though most were of little clinical significance, in some patients the errors may have put the patients at risk either for relapse or for overdose-related complications.

In the United States medical errors cause up to 98,000 hospital deaths per year more deaths than by motor vehicle accidents and breast cancer combined. Medication errors are attributable to almost 7,000 inpatient deaths. Medication errors in the outpatient setting are thought to be some of the most common medical errors, but they are not well-studied, particularly in children. These mistakes can occur in prescribing by physicians, during interpretation and processing by pharmacists, and when administered by patients or their caregivers. Most mistakes among outpatients are caught before drugs are given to patients, and because most drugs have wide safety ranges, most errors are benign. Children with cancer, however, receive extremely toxic drugs with narrow safe dose ranges and must be prescribed according to specific, sometimes complex, protocols.

Led by James A. Taylor, M.D. of the University of Washington and Children's Hospital and Regional Medical Center in Seattle, researchers studied the rate and types of medications errors that occur in children receiving outpatient chemotherapy regimen for ALL. The authors reviewed the administration of drugs and the medications prescribed and dispensed to 69 enrolled patients.

One or more errors were identified in 17 of 172 (9.9 percent) chemotherapeutic medications and impacted 13 of 69 (19 percent) pediatric patients. Of the 17 errors, 12 were attributed to how the medications were administered to the patient, and 5 were attributed to prescribing errors that is, incorrect dosages. There were no dispensing errors by a pharmacy.

Though there was little clinical impact of the errors in 9 of the 13 patients, errors in 4 children were potentially clinically significant. Three patients failed to receive medications at the appropriate time, increasing the risk of relapse. One patient received an overdose of medication and, consequently, was at greater risk for life-threatening infection.

This study identified a 10 percent error rate in outpatient chemotherapy regimens for children with ALL. "It is possible that the efficacy of treatment regimens is reduced or toxicity increased because not all children are receiving the chemotherapeutic agents as indicated," said Dr. Taylor. Moreover, the authors recommended, "in designing new [chemotherapy] protocols, a balance needs to be struck between the precision of dosing regimens and simplification so that medication errors are minimized."

JAK-STAT pathway inhibitors are likely to be effective against some leukemias

Mon, 24 Jul 2006 23:28:00 PST

( from http://www.rxpgnews.com ) New research indicates that drugs that target a cell growth pathway known as the JAK-STAT pathway are likely to be effective against certain chronic leukemias.

Researchers recently discovered that a mutation in the JAK2 gene is responsible for the majority of cases of three rare kinds of chronic leukemia, all of which are resistant to the leukemia drug Gleevec. The new study identifies a second mutation in the same pathway that can also cause the disease, leading researchers to think that drugs targeting JAK-STAT signaling should be effective against leukemias caused by either mutation.

In a study published July 18, 2006, in the online journal Public Library of Science Medicine, a team led by Yana Pikman, a Howard Hughes Medical Institute (HHMI) medical research fellow, and Ross L. Levine, a former HHMI medical research fellow, found a mutation in a gene called MPL in a subset of leukemias that lacked the more common JAK2 mutation. HHMI medical research fellows are medical students who compete for the opportunity to spend a year doing full-time research.

D. Gary Gilliland, an HHMI investigator at Brigham and Women's Hospital and Harvard Medical School, is co-author of the paper.

"We're excited about this finding because we hope to identify a common drug, an inhibitor of the JAK2 pathway, to treat patients with these types of leukemia," said Gilliland, who in 2005 worked with Levine to identify the JAK2 mutation responsible for most cases of myelofibrosis (MF), polycythemia vera (PV), and essential thrombocytosis (ET).

JAK2 normally encodes a protein that helps control the production of new blood cells. But when the gene is mutated, JAK2's growth-stimulating signal gets turned on permanently, causing overproduction of one or another type of blood cell. In different forms of the disease, the overabundant cells may be various kinds of white blood cells, platelets, or oxygen-carrying red blood cells.

Over time, this overproduction disrupts the balance of cells in the blood, hampers normal immune responses, overcrowds the bone marrow to make it dense and stiff, and forces blood formation to shift to the spleen and liver. Eventually those two organs become grossly enlarged; the end result is death.

Thus, the JAK2 pathway is an important player in leukemia. Levine, Pikman, and Gilliland's new work shows that the pathway can be activated without a mutation in the JAK2 gene itself. The new mutation they found lies in a gene called MPL. MPL encodes a receptor protein that sits on the surface of some blood cells and receives growth signals, communicating to JAK2 when a signal has arrived. Mutated MPL, however, constantly tells JAK2 to trigger growth--whether or not the appropriate signal has reached the cell. Thus, the end result is the same as that of a mutation that activates JAK2 directly: uncontrolled growth and an imbalance of blood cells.

"Now we have two targets that may be useful in the search for drug treatments to control chronic leukemia," said Pikman, lead author of the PLoS Medicine article and a student at Harvard Medical School. "This new mutation is interesting because when we express it in mice, they get a very similar disease, so it may be a good model for testing drugs against leukemia," Pikman added. She said a search is already under way to identify small molecules that might be effective in overcoming the damage caused by the mutations.

The leukemias that the researchers study cannot be controlled by Gleevec, one of the first treatments that targets a known molecular defect. Gleevec, developed by HHMI investigators Brian J. Druker and Charles L. Sawyers, is very effective against the most common form of chronic leukemia, chronic myelogenous leukemia (CML), but there are many cases of chronic leukemia that Gleevec cannot control. Gleevec works by targeting the Philadelphia chromosome, a mutation that triggers excessive cell growth in many leukemias but does not exist in MF, PV, and ET.

The first mutation in JAK2 stimulating the JAK-STAT pathway was discovered in 2005 by Gilliland and Levine, an instructor at Harvard Medical School and the senior author of the PLoS Medicine paper, and was also reported by several other laboratories in the United Kingdom, France, and Switzerland. That first mutation accounts for about half of the patients who have the three sub-types of chronic leukemia that Gleevec cannot control.

"But we had found a significant number of patients who didn't have that mutation," Levine said. "So this (new discovery) represents our first insight into the cases not attributable to the first mutation. It doesn't explain all of them, but it tells us more about this whole family of disorders." Gilliland said there probably are other mutations in the same pathway that explain additional cases of leukemia.

HO-1 in sickle cell disease

Wed, 19 Jul 2006 03:33:00 PST

( from http://www.rxpgnews.com ) Rochester, Minnesota -- Researchers have unexpectedly shown that sickle cell-associated kidney injury may be reduced by inhibiting the enzyme activity of a protein that commonly confers protection in other diseased states. The paper by Juncos et al., "Anomalous renal effects of tin protoporphyrin in a murine model of sickle cell disease," appears in the July issue of The American Journal of Pathology.

Sickle cell disease (SCD), which affects greater than 70,000 individuals in the US, is an inherited hemoglobin disorder that causes some red blood cells to lose their smooth round shape and assume a crescent, or sickle, shape. Sickle cells can become lodged in small capillary blood vessels, with blockage of blood flow leading to pain, stroke, and damage to most organs including the lungs, spleen, kidneys and liver.

The mechanisms underlying SCD-associated kidney disease include various forms of secondary stress, such as changes in internal kidney blood flow, induction of oxidative injury, and influx of inflammatory cells. Researchers have thought that cells combat such stress through expression of heme oxygenase-1 (HO-1), a protective enzyme that is upregulated in SCD kidneys in humans and in mouse models. New research, however, suggests that in SCD HO-1 may not be as protective as previously thought.

In an attempt to understand the specific role of HO-1 in kidney injury, Juncos et al. examined SCD mice in the presence or absence of tin protoporphyrin (SnPP), a widely accepted inhibitor of the enzyme activity of HO. Short-term SnPP treatment successfully blocked HO activity in both normal and SCD mice, reduced kidney blood flow in normal and SCD mice, but did not affect the filtration capacity of the kidney in either group. However, when chronically administered, SnPP caused inflammation and fibrosis (scarring) in normal mice but not in SCD mice; in normal mice, SnPP induced genes related to fibrosis and inflammation, whereas in SCD mice, these genes were downregulated.

The scientists next examined the effect of SnPP on kidney injury induced by temporarily interrupting kidney blood flow (ischemia); the kidney in SCD mice is hypersensitive to such ischemia. Surprisingly, when mice were treated with SnPP, SCD kidneys were protected from ischemia-induced cell death and blood vessel blockage whereas normal kidneys exhibited cell death and injury. Thus, in contrast with its effects observed in normal mice, SnPP protected SCD kidneys from injury.

In other diseases, induction of HO-1 is protective by generating products such as carbon monoxide and bile pigments, both of which can reduce tissue injury; however, in larger amounts, these products may be toxic. It is possible that the degree of induction of HO-1 in SCD may generate toxic rather than protective amounts of these products. Additionally, along with its intended effect of inhibiting HO activity, SnPP may induce HO-1 protein, and this latter effect may underlie the observed cytoprotection. Finally, besides inhibiting HO activity, SnPP may concomitantly interrupt other pathways, independent of the HO system, that contribute to kidney injury in SCD.

In the process of analyzing the biologic significance of HO-1 in SCD, Juncos et al. uncovered an experimental strategy that reduced kidney injury in a mouse model of SCD. Further work will likely delineate the basis for the protective effects of SnPP in SCD, specifically, the dependency on inhibition of HO activity, increase in HO-1 protein, or some other as-yet-undefined mechanism.

Dasatinib treats resistant cases of CML

Thu, 15 Jun 2006 11:29:00 PST

( from http://www.rxpgnews.com ) An experimental therapy that battles drug resistance in Chronic Myeloid Leukemia (CML) has proved "extremely effective" in fighting cancer, giving patients for whom all conventional therapies have failed another option, researchers at UCLA's Jonsson Cancer Center reported.

The Bristol-Myers Squibb therapy, Sprycel (dasatinib), treats CML that has mutated and becomes resistant to the leukemia pill Gleevec, said Dr. Charles Sawyers, a professor of hematology/oncology, a Jonsson Cancer Center researcher and lead author of the study, published in the June 15, 2006 issue of the peer-reviewed New England Journal of Medicine.

The results are from a Phase I study of Sprycel. The early results were so favorable that several Phase II studies were launched last year and are almost completed. Because these trials have moved so quickly and because more positive results are anticipated, an advisory panel for the U.S. Food & Drug Administration on June 2 recommended that the agency approve the drug, which could happen before the end of the month, Sawyers said. Like Gleevec, Sprycel also is taken in pill form.

Sawyers characterized the Phase I study results as remarkable, saying the first human trial confirmed the pre-clinical laboratory work and scientific discovery done at UCLA's Jonsson Cancer Center, where the mechanisms and mutations behind Gleevec resistance were uncovered. The Phase I study was done jointly with MD Anderson Cancer Center.

"This shows that if you have a precise molecular understanding of a drug target you can very quickly decipher the reasons for response and failure to therapy and quickly come up with backup treatment strategies," said Sawyers, a Howard Hughes Medical Institute investigator. "Gleevec remains a spectacular step forward in the field of targeted therapy. However, some patients develop resistance to the drug after several years of therapy. These patients now have another effective option in this drug."

Drug development often can take decades. However, it has been just five years since Gleevec was approved. In that time, UCLA scientists were able to discover how the CML in some patients mutated and became resistant to Gleevec and test an existing compound on laboratory models and then in patients with great success.

Resistance in CML patients is associated with mutations in the Bcr-Abl gene that interfere with the drug's mechanism of action. Sprycel blocks 14 of 15 documented CML mutations known to lead to resistance, Sawyers said. It's about 300 times more potent than Gleevec as well.

Over five years, about 20 percent of patients become resistant to Gleevec, Sawyers said. One of the reasons Sprycel works so well to combat that resistance is that it binds to the mutant proteins in a different way than Gleevec, and it also inhibits several other tyrosine kinases believed to play roles in cancer growth, Sawyers said.

"The main message is that this drug is extremely effective in CML patients who have failed all standard therapy including Gleevec," Sawyers said. "The basic science findings all panned out. What we predicted based on laboratory studies proved true in human trials. While there was some concern that this drug might be more toxic because it is more potent, we are delighted to find that it is very well tolerated."

The UCLA Phase I study enrolled 84 patients 40 with chronic phase CML, 11 with accelerated phase CML, a more serious form of the disease, and 23 whose CML was in blast crisis, the last and most serious phase of CML. Additionally, 10 patients with acute lymphoblastic leukemia (ALL) were enrolled because they tested positive for the Philadelphia chromosome, the genetic abnormality that characterizes most cases of CML and the primary mutation targeted by the drug.

A major cytogenetic response - a substantial reduction in cells containing the Philadelphia chromosome in the bone marrow - was found in 45 percent of chronic phase patients, Sawyers said. In the patients with accelerated and blast phase CML and in patients with ALL, a major cytogenetic response was reported in 43 percent of patients. The responses have lasted for up to two years in some cases and although the study is complete, a number of patients continue to take the drug and are still being monitored.

Sawyers said it's possible that Gleevec and Sprycel might be used together in patients with CML as a very effective one-two punch to fight cancer and battle drug resistance.

Lakewood resident Kevin Williams, 41, married and a father of two, was diagnosed with CML in June of 2000. He was put on interferon, the standard treatment for CML at that time. The side effects were brutal . Williams felt as if he had a bad flu all the time. He lost weight and was constantly tired. When it became clear that the interferon was not working, Williams' UCLA oncologist prescribed Gleevec, which had just been approved by the FDA.

After about 10 months on Gleevec, Williams and his oncologists noticed that he was becoming resistant to the drug. His white blood cell count was more difficult to maintain and Williams had to take more and more Gleevec to achieve a stable response. And he was showing no cytogenetic response at all. The mutated cells in his bone marrow that were causing his CML were not decreasing in number. In June 2005, Williams enrolled in a Jonsson Cancer Center study of Sprycel. A bone marrow test in February surprised Williams and his oncologists there was absolutely no evidence in his marrow of the mutated cells. Williams was 100 percent negative for cancer just nine months after he started taking Sprycel.

"I feel like this drug has given me my life back again," said Williams, a computer programmer. "I can now do all the things I used to do before. I feel great."

Williams has returned to his active life, going snow skiing and road racing his motorcycle. He also spends quality time with his wife, Teresa, and his daughter, Kerri, 13, and son, Brian, 7.

HBZ protein enhance ability of HTLV-1 to establish persistent infection

Mon, 12 Jun 2006 19:56:00 PST

( from http://www.rxpgnews.com ) A protein made by a cancer-causing virus using an unusual gene enables that virus to infect immune cells and persist in the host, new research shows.

The study examines the function of a protein called HBZ, which is made by the human T cell leukemia virus type 1 (HTLV-1), a retrovirus and a distant cousin to HIV, the cause of AIDS. The findings indicate that HBZ enhanced the ability of HTLV-1 to establish a persistent infection in an animal host. The study by researchers with the Ohio State University Comprehensive Center and the College of Veterinary Medicine is published in the May issue of the journal Blood.

The gene that gives rise to HBZ is unusual because it lies on the wrong side of the virus's DNA molecule. Such genes are known as antisense genes, and they have been observed in only a few retroviruses, including HIV.

A DNA molecule is somewhat like a railroad track that is twisted into a double helix. The two rails correspond to the complementary strands of the DNA backbone, while the ties correspond to the chemical base pairs that hold the two strands together and encode genetic information.

Normally, that genetic information is encoded only along one DNA rail, or strand. That strand is called the sense strand. The opposite strand is the antisense strand, and it generally carries no genetic information.

But HTLV-1 is a rare exception. Of its eight genes, (some of which have information for more than one protein), seven lie along the sense strand. The eighth, which encodes the HBZ gene, is on the antisense strand (where it lies across from portions of three genes on the sense strand). Encoding a gene on the antisense strand is one more way for a small, compact virus to pack more genetic information or genes into a very small space, and it is why viruses like HTLV and HIV are called complex retroviruses, says principal investigator Patrick L. Green, professor of veterinary biosciences and of molecular virology, immunology and medical genetics, and a Comprehensive Cancer Center researcher.

Our study is the first to show that this novel protein is important for survival of the virus, which suggests that a drug that targets it might disrupt viral replication and provide a new therapy for infected people.

Some 15 to 25 million people are infected with HTLV-1 worldwide, and 1 to 4 percent of them will eventually develop adult T-cell leukemia or lymphoma, a cancer that responds poorly to treatment and that can cause death within six months. In others, it causes a crippling and painful autoimmune-like disorder, tropical spastic paraparesis.

For this study, Green and his collaborators first looked at how loss of the HBZ protein affected the virus's ability to infect and survive in its normal host immune cell, human T lymphocytes, or T cells, growing in culture.

They found little difference between the HBZ mutant HTLV and the normal virus. Both infected the cells and immortalized them equally well.

(Normally, T cells in culture die within a week or two. When the same cells are infected with HTLV-1, however, the virus causes changes that extend their life span indefinitely.)

Next, the scientists tested the ability of the mutant virus to infect and persist in a rabbit model, one of the few animals that duplicates human HTLV-1 infection. Those results indicated that the HBZ protein was required for prolonged infection in the body.

After eight weeks, rabbits that were infected with virus that lacked HBZ had one to 10 copies of the virus per 1,000 lymphocytes, whereas rabbits infected with normal virus had 50 to 100 HTLV-1 copies per 1,000 lymphocytes.

The virus may not survive well without HBZ because the immune system readily destroys cells infected by these viruses, Green says.

We believe that HBZ acts as a brake on viral replication, he says. Without HBZ, the virus replicates too fast, producing its proteins so quickly that the immune system readily detects infected cells and eliminates them.

Green and his colleagues are now testing that hypothesis.

Gene expression signature for Burkitt lymphoma identified

Sat, 10 Jun 2006 13:47:00 PST

( from http://www.rxpgnews.com ) An international research study involving the University of Nebraska Medical Center, the National Cancer Institute and 10 other institutions has successfully identified the gene expression signature for Burkitt lymphoma. The discovery, which is reported in the June 8 edition of The New England of Medicine, will allow physicians to better diagnose and treat Burkitt lymphoma and better distinguish it from another more common form of malignant lymphoma.

Burkitt lymphoma is a rare aggressive B cell lymphoma that accounts for 30 to 50 percent of lymphomas in children but only 1 to 2 percent of lymphomas in adults. Burkitt lymphoma is rapidly fatal if untreated, but it is curable with intensive therapy.

Burkitt lymphoma features a high degree of proliferation of the malignant cells and deregulation of the c-myc gene, which is characteristic of Burkitt lymphoma. The distinction between Burkitt lymphoma and diffuse large B cell lymphoma (DLBCL), the most common form of non-Hodgkins lymphoma in adults, is critical, because the management of these two diseases differs. About 300 new cases of Burkitt lymphoma, typically in children, are diagnosed in the U.S. each year.

Whereas a relatively low-dose chemotherapy regimen is typically used to treat DLBCL, this regimen is inadequate for Burkitt lymphoma, which requires intensive chemotherapy. In addition, because of the high risk of central nervous system involvement with Burkitt lymphoma, it is essential that intrathecal or systemic chemotherapy that crosses the blood-brain barrier be administered. This type of chemotherapy is unnecessary in most cases of DLBCL.

The article in The New England Journal of Medicine featured the results of two studies on the molecular diagnosis of Burkitt lymphoma involving several European and North American institutions. One of the research teams was led by Wing (John) Chan, M.D., the Amelia and Austin Vickery Professor of Pathology and co-director of the Center for Lymphoma and Leukemia Research at UNMC, and Louis Staudt, M.D., Ph.D., head of the molecular biology of lymphoid malignancies section at the National Cancer Institute. The research was supported through a multi-million dollar Director Challenge Grant awarded to Dr. Chan by the National Cancer Institute.

Our group studied the gene expression profiles of 71 previous, untreated HIV-negative patients with sporadic Burkitt lymphoma or Burkitt-like lymphoma, said Kai Fu, M.D., Ph.D., assistant professor, pathology and microbiology, at UNMC and the second author of the study. We successfully identified a gene expression signature for Burkitt lymphoma that clearly distinguishes Burkitt lymphoma from DLBCL.

Using the gene expression signature for Burkitt lymphoma, the group was readily able to distinguish Burkitt lymphoma from DLBCL by the high expression of the c-myc target gene as well as a subset of other target genes.

Overall survival was markedly superior for patients with a molecular diagnosis of Burkitt lymphoma, as they were given an intensive chemotherapy regimen instead of a lower dose regimen. Notably, eight cases given a pathological diagnosis of DLBCL were re-classified by gene expression as Burkitt lymphoma. These cases had all the gene expression hallmarks of Burkitt lymphoma, suggesting that they represent cases of Burkitt lymphoma that are difficult to diagnose by current methods.

The study results would suggest that gene expression profiling is an accurate, quantitative method to distinguish Burkitt lymphoma from DLBCL, Dr. Fu said. This study gives us another example of the usefulness of gene expression profiling for defining biologic entities with important implications for clinical research and practice, he said.

Bcr-Abl mutation and the loss of Arf genes triggers an aggressive form of ALL

Thu, 20 Apr 2006 16:46:00 PST

( from http://www.rxpgnews.com ) Investigators at St. Jude Children's Research Hospital have used mouse models to determine why some forms of acute lymphoblastic leukemia (ALL) are extremely aggressive and resist a drug that is effective in treating a different type of leukemia.

The investigators found that the combination of a mutation called Bcr-Abl and the loss of both copies of the tumor suppressor gene Arf in bone marrow cells triggers an aggressive form of ALL. Inactivation of both Arf genes facilitated the multiplication of leukemic cells that did not respond to the drug imatinib (Gleevec®). Imatinib is already successfully used to treat chronic myelogenous leukemia (CML), another blood cell cancer caused by the Bcr-Abl mutation.

The St. Jude study provided evidence that imatinib resistance in mouse models of ALL did not depend strictly on the presence of Bcr-Abl and the loss of Arf genes in the cancer cells themselves. Rather, drug resistance reflected an interaction of the tumor cells with specific growth-promoting factors produced in the mice. After removal of leukemic cells from mice that had failed imatinib therapy, compounds inhibiting enzymes called JAK kinases restored the cells' imatinib sensitivity.

The study's findings suggest why imatinib may fail to cause remission of ALL in patients with the Bcr-Abl mutation and point to a strategy for overcoming this resistance.

The Bcr-Abl oncogene (a cancer-causing gene) is formed when parts of two chromosomes switch places, leading to fusion of a fragment of the Bcr gene from one chromosome to a portion of the Abl gene from the other. Bcr-Abl encodes a type of enzyme called a tyrosine kinase, which then drives the abnormal, uncontrolled multiplication of leukemic cells.

Other researchers had previously shown that inhibiting the Bcr-Abl kinase with imatinib causes durable remissions of cancer with minimal side effects in patients with CML--a finding that has revolutionized the treatment of this form of leukemia. However, imatinib has proven far less effective in treating ALL patients with the Bcr-Abl mutation, and the basis of drug resistance in this disease is unknown.

The Arf gene normally suppresses the proliferation of cells carrying cancer-causing mutations such as Bcr-Abl, according to Charles J. Sherr, M.D., Ph.D., a Howard Hughes Medical Institute investigator and co-chair of the St. Jude Department of Genetics and Tumor Cell Biology. Arf acts as a safeguard against the cancer-causing effects of Bcr-Abl, Sherr said. Sherr is senior author of the paper. The Arf gene was discovered at St. Jude in 1995 in the laboratory of Sherr and Martine F. Roussel, Ph.D., a member of the Department of Genetics and Tumor Cell Biology. Roussel is also an author of the current paper.

The St. Jude team found that Arf is not inactivated in CML patients who respond to imatinib. This is in contrast to ALL, in which Arf loss frequently occurs and imatinib treatment is far less effective. "This suggested to us that inactivation of Arf in ALL cells expressing the Bcr-Abl enzyme gives these cells a strong proliferative (cell multiplication) advantage," Sherr said. "And this advantage might contribute to imatinib resistance in some way."

To investigate this hypothesis, the researchers used a virus-like piece of DNA to carry the Bcr-Abl oncogene into bone marrow-derived lymphocytes obtained from mice that either retained Arf or were previously engineered to lack this gene. These pre-B lymphocytes represent one type of white blood cell that can become cancerous and cause ALL.

The researchers then transplanted these "transformed" cells carrying Bcr-Abl back into normal mice. Animals that received transformed pre-B cells that had both copies of the Arf gene intact were highly resistant to disease development. However, mice injected with cells that carried Bcr-Abl and lacked Arf rapidly developed an aggressive form of ALL that could not be cured with high doses of imatinib.

"Intriguingly, tumor cells removed from these resistant mice and treated with imatinib in cell cultures were still very sensitive to this drug," noted Richard T. Williams, M.D., Ph.D., a fellow in Sherr's laboratory and the paper's lead author. "This suggested to us that the failure of imatinib to cure the mice depended on some substance in the animal that stimulated tumor cell replication or survival."

Sherr's team guessed that one such factor might be the B lymphocyte stimulating protein IL-7. Normally produced in the bone marrow, IL-7 further enhanced the proliferation of cultured leukemic cells removed from the mice and made the cells resistant to imatinib's growth inhibitory effects.

IL-7 binds to receptors on the surface of lymphocytes, which triggers the activity of the JAK kinases. The activated JAK kinases then stimulate cell growth through a signaling pathway that operates alongside the one controlled by the Bcr-Abl kinase, Sherr said. Therefore, the St. Jude investigators used a chemical inhibitor of JAK kinases to block the effect of IL-7 on leukemic cells in culture. This treatment restored the ALL cells' sensitivity to imatinib.

"Our study of mice with ALL containing both Bcr-Abl and Arf mutations has provided unexpected insights into how factors in the mice--and potentially in humans--might contribute to imatinib resistance," Williams said. "Although our efforts to block IL-7 were limited to cell cultures, our mouse model provides an inexpensive and efficient way to test newly developed JAK kinase inhibitors and other drugs."

New simple and inexpensive test for follow-up of acute lymphoblastic leukemia (ALL)

Thu, 30 Mar 2006 15:14:00 PST

( from http://www.rxpgnews.com ) Investigators at St. Jude Children's Research Hospital have developed a relatively simple and inexpensive test that identifies children with acute lymphoblastic leukemia (ALL) who have responded well enough to their first round of chemotherapy that they might be successfully treated with a much less aggressive follow-up treatment.

The new test could give hospitals with limited resources an affordable way to improve the outcome of ALL treatment for many children by reducing chemotherapy side effects.

The test measures minimal residual disease (MRD)--the small number of leukemic cells that survive after remission induction therapy. This measurement helps clinicians identify patients whose disease is highly responsive to chemotherapy and those who might be cured with milder and less toxic treatment.

The study found that the new test provides results that are acceptably close to those obtained with more complex and expensive MRD tests, which can be performed only at a few cancer centers worldwide. The new assay uses only one test tube with three probes that can distinguish leukemic cells from normal cells in the bone marrow of children with ALL taken after two weeks of chemotherapy, according to the paper's senior author, Dario Campana, M.D., Ph.D., a member of the St. Jude Hematology-Oncology and Pathology Departments.

The high cost and complexity of the more sophisticated MRD tests have impeded their use in countries with limited resources, Campana said. "That limited the number of children who could benefit from MRD assays," he said. "The test we developed will allow clinicians at institutions with limited resources to reliably identify children who could be spared the harsh side effects caused by intense chemotherapy."

The investigators used the new test to examine bone marrow cells collected from 380 children with B-lineage ALL 19 days after the beginning of remission induction therapy. In 211 patients (55.5 percent), the test determined that leukemic cells made up 0.01 percent or more of the cells in the sample. This result closely agreed with the results from the more expensive and complex tests, said Elaine Coustan-Smith, an associate scientist in the same departments and the paper's first author.

The researchers reported that among the patients with 0.01 percent or more of leukemic cells detected by the simplified test on day 19, the incidence of relapse was about 29 percent after 10 years; among patients with levels of leukemic cells lower than 0.01 percent, the incidence of relapse was about 5 percent. The results obtained using the simplified test more accurately predicted whose disease would relapse and whose would respond well to chemotherapy than did standard risk factors, such as age and the presence of certain mutations in the cancer cells.

The St. Jude International Outreach Program (IOP) is now implementing this new test at a partner institution in Brazil, according to the paper's co-author, Raul Ribeiro, M.D., a member of the Department of Hematology-Oncology and IOP director. The pilot project in Recife, Brazil, aims to identify children who have MRD levels lower than 0.01 percent on day 19 so they can be treated with therapy that is less intense than the standard treatment. Previously, 10 percent of the children in Recife receiving standard therapy suffered fatal infections because of immune system suppression caused by the aggressive treatment, Ribeiro noted. Therefore, in addition to improving supportive care for patients, investigators in Recife sought to reduce the intensity of treatment for a select group of patients.

"Clinicians have known since the 1970s that about 40 percent of children with ALL can be cured with less intense therapy," Ribeiro said. "The problem is identifying those children who will be cured with less intense treatment so you can avoid or lessen the complications caused by aggressive therapy. The new MRD test developed at St. Jude can be used to identify patients who might be cured with less intensive treatment approaches. This will decrease the toxicity and the cost of treatment. Hence, we anticipate that the use of our new technique will increase the number of children who can be treated, and reduce the number of children who suffer fatal infections."

miRNAs abnormal signalling may lead to platelet-related leukemias

Thu, 16 Mar 2006 22:01:00 PST

( from http://www.rxpgnews.com ) Scientists have identified a handful of microRNAs (miRNAs) that appear to play a significant role in the development of platelets blood cells critical to the bodys ability to form clots following an injury. They also say some of these same miRNAs, when acting abnormally, may contribute to certain forms of leukemia.

Basically, we found that a specific set of miRNA genes are turned off in normal platelet development, but turned on in certain platelet-related leukemia cells, says lead author Dr. Ramiro Garzon, a clinical instructor in The Ohio State University College of Medicine.

The study is published online in the Proceedings of the National Academy of Sciences.

MiRNA has only recently been acknowledged as an important force in biology. For decades, scientific dogma has held that messenger RNA (mRNA) was responsible for carrying out DNA instructions, or code, for protein production in the cell. Little was known, however, about how cells actually regulated that process. But over the past 10 years, researchers have discovered that miRNA tiny fragments of RNA typically no more than 20-25 nucleotides in length also regulates protein synthesis by interfering with mRNAs original instructions. They now know that miRNA helps to regulate many key biological processes, including cell growth, death, development and differentiation.

Dr. Carlo Croce, director of Ohio States Human Cancer Genetics Program, was the first to discover a link between miRNA and cancer. In the current study, Croce, who is also a member of the OSU Comprehensive Cancer Center, along with Garzon and colleagues from the M.D. Anderson Cancer Center, examined miRNA activity in the earliest phases of platelet development.

The researchers had previously uncovered substantial evidence linking certain patterns of miRNA to both normal and abnormal blood cell development, especially in diseases like chronic lymphocytic leukemia and lymphoma. Relatively little was known, however, about miRNA functionality in platelet formation.

Platelets are created from stem cells in the bone marrow. They evolve through a process called megakaryocytopoiesis, which generates megakaryocytes, or platelet parent cells.

The research team used microRNA gene chip analysis to identify miRNA expression in normal stem cells and megakaryoctyes. They also studied miRNA expression patterns in four acute megakaryoblastic leukemia (AMKL) cell lines. They discovered that a set of 17 miRNAs are turned off during normal megakaryocyte differentiation and that 8 of those genes create a molecular signature that clearly defines a megakaryocyte from any other type of cell.

We believe this set of genes may contribute to platelet formation, says Garzon. We think that when these miRNAs are turned off, its a signal to other gene targets to get busy with the normal process of development. Garzon says just the opposite happens in AMKL, an unusual form of leukemia more often found in children than adults.

In examining four sets of AMKL lines, they found that 10 miRNAs were turned on, again representing a molecular signature for that disease. Interestingly, half of that number are also members of the miRNA profile in normal platelet cell development suggesting that this small subset may be most important in understanding how AMKL develops, says Garzon.

Researchers believe that more knowledge about miRNA could lead to a new class of targeted therapies that may be helpful in treating leukemia and other diseases. That day, however, is still a long way off, says Garzon.

DNA itself can act as a mutagen

Sun, 12 Feb 2006 18:01:00 PST

( from http://www.rxpgnews.com ) When otherwise normal DNA adopts an unusual shape called Z-DNA, it can lead to the kind of genetic instability associated with cancers such as leukemia and lymphoma, according to a study by researchers at The University of Texas M. D. Anderson Cancer Center.

The study, issued in advance of the Feb. 21 edition of the Proceedings of the National Academy of Sciences, demonstrates for the first time that the oddly shaped DNA can cause DNA breaks in mammalian cells. Interestingly, these sequences prone to forming Z-DNA are often found in genetic âhot spots,â areas of DNA known to be prone to the genetic rearrangements associated with cancer. About 90 percent of patients with Burkittâs lymphoma, for example, have DNA breaks that map to regions with the potential to form these odd DNA structures.

âOur study shows that DNA itself can act as a mutagen, resulting in genetic instability,â says Karen Vasquez, Ph.D., lead author of the study and assistant professor of carcinogenesis at
M. D. Andersonâs Science Park Research Division, Smithville, Texas. âThe discovery opens up a new field of inquiry into the role of DNA shape in genomic instability and cancer.â

Imagine untwisting the DNA ladder and then winding it up the other way. The result is a twisted mess with segments jutting out left and right, and the all important base pairs that hold the DNA code zigzagging in a jagged zipper shape. Scientists call this left-hand twist Z-DNA. This is a far cry from the graceful right-hand twisted helix that has become an iconic symbol of biology. It just doesnât look right, and it doesnât act right either, according to Vasquez. This awkward shape puts strain on the DNA, and as Vasquez and her colleagues show, can cause the DNA molecule to break completely apart.

Scientists have known for many years that DNA can take shapes other than the typical twisted ladder form, but they werenât sure how often these alternate shapes occur inside cells.

Researchers who study these shapes had previously shown that Z-DNA can form only at certain DNA sequences because the shapes of the bases themselves contribute to Z-DNA formation. For example, the sequence CG repeated more than 14 times in a row is prone to forming Z-DNA, while the sequence AT is not as efficient at forming this structure. Analysis of the genome reveals that DNA sequences prone to forming the Z-DNA structure occur in 0.25 percent of the genome, according to Vasquez.

She and her colleagues decided to find out whether Z-DNA itself had any effect on the DNA stability. To do that, post-doctoral fellow Guliang Wang, Ph.D., made pieces of DNA designed to form the Z-DNA shape. The researchers then introduced these segments of DNA, called plasmids, into bacterial cells and human cells in the laboratory. They then broke apart the cells and examined what happens to the DNA. They found that in bacterial cells, the Z-DNA caused small deletions or insertions of one or two DNA bases. But in human cells, the introduced Z-DNA led to large-scale deletions and rearrangements of the DNA molecule.

âWe discovered that bacterial cells and human cells process the Z-DNA in different ways,â she says. âWe arenât sure why, but we think that the DNA repair machinery may be involved in processing the Z-DNA structure differently in bacteria versus human cells.â

Since formation of Z-DNA is naturally occurring and can exist in the genome, the scientists next want to understand why cells can sometimes process the structure without creating double-stranded breaks. They also want to know why certain places in the genome become âhot spotsâ for these breaks, while other seemingly similar areas do not.

âIf we could understand the players involved in this process, we might be able to prevent the generation of these breaks,â says Vasquez. âFor example, if certain types of cell stress lead to breaks, we might be able to find ways to reduce those stresses and prevent breaks.â

Senior research assistant Laura Christensen also contributed to the research. The study was supported by grants from the National Cancer Institute and the National Institute of Environmental Health Sciences, as well as an Odyssey fellowship to Guliang Wang from M. D. Anderson Cancer Center.

New Drug VX-680 May Overcome Deadly Leukemia Mutation

Fri, 20 Jan 2006 22:08:00 PST

( from http://www.rxpgnews.com ) HHMI researchers have discovered how a new generation of drugs thwarts a deadly mutation that causes chronic myelogenous leukemia (CML).

Although the drug Gleevec, which is manufactured by Novartis, is considered the standard of treatment for CML, certain patients develop resistance to the drug. Resistance is usually caused by mutations that alter the shape of an enzyme called Abl that is targeted by Gleevec. Using x-ray crystallography, the scientists produced detailed molecular images that reveal how VX-680, a drug developed by Vertex Pharmaceuticals and Merck, interacts with a mutant form of Abl. The new studies, published in the January 15, 2006, issue of the journal Cancer Research, hint at how VX-680 jams the mutant Abl enzyme and stops proliferation of cancerous cells. One of the more problematic mutations in Abl is called T315I, and it is responsible for about 15 percent of cases in which CML patients develop resistance to Gleevec. The T315I mutation also confers resistance to dasatinib, a newer drug developed by Bristol-Myers Squibb that has been effective in phase I and phase II trials as a second line of defense in patients who develop resistance to Gleevec. The T315I mutation is particularly troublesome because it sits at the heart of the enzyme's catalytic center, said Kuriyan, and blocks the binding of Gleevec and dasatinib.

We found that dasatinib overcomes all of these Gleevec-resistant mutants, with the exception of T315I. So, the remaining unturned stone has been to find a drug to treat T315I.

That new knowledge could aid in developing a strategy for searching for other drugs that could inhibit resistant mutants.

Abl is an enzymatic switch called a kinase that becomes overactivated by a chromosomal mix-up that occurs during blood cell development. The genes ABL and BCR, which are located on different chromosomes, become fused and express a hybrid Bcr-Abl enzyme that is always active. In earlier studies, Sawyers and his colleagues showed that dasatinib could overcome a significant proportion of the resistant mutants.

In the experiments reported in the Cancer Research article, Kuriyan and his colleagues used x-ray crystallography to produce molecular images that give researchers a better idea of how VX-680 binds to the T315I mutant version of Bcr-Abl. While the researchers were not able to create useful crystals of the complex of VX-680 with a T315I mutant Bcr-Abl, the current studies show the structure of VX-680 in complex with another Abl mutant, H396P, which is resistant to Gleevec.

The Abl kinase, like other kinases, can assume active or inactive conformations, and the researchers' structural analysis revealed that the H396P mutation caused the enzyme to favor an active conformation. The researchers found that VX-680 was effective at blocking this mutant because it could recognize and bind to an active conformation, said Kuriyan. In contrast, Gleevec and dasatinib act by recognizing an inactive conformation and binding to it, rendering the Abl kinase inactive.

Thus, this structure does help explain why VX-680 has activity against the T315I mutation, and that arises from the shape of VX-680, said Kuriyan. While Gleevec penetrates deeply into the kinase domain of Abl, VX-680 stays away from the position of the T315I mutation, leaving a significant gap. This gap allows VX-680 to accommodate the mutation and still bind to the mutant Abl.

In additional experiments, Sawyers and his colleagues tested VX-680's effectiveness against CML cells isolated from a patient with the T315I mutation. The studies showed that the drug inhibited T315I mutant BCR-ABL in the cancer cells.

This offers a very useful predictive tool that tells us that the drug does work against the mutation, said Sawyers.

Garden insecticides may increase leukaemia risk

Wed, 18 Jan 2006 00:22:00 PST

( from http://www.rxpgnews.com ) Household insecticides may increase the risk of leukemia, says a new study, reinforcing the theory that pesticide exposure may play a role in childhood acute leukaemia.

Florence Menegaux and other researchers of Inserm Medical Research Institute in France studied 568 children, half of whom had acute leukaemia. They asked them about employment history of both parents and the use of insecticides in their homes and gardens.

They found use of home insecticides during pregnancy and childhood increased the risk of leukaemia by nearly twice, reported online edition of BBC News. A similar risk was also seen for the use of insecticidal shampoo to treat head lice.

Use of garden insecticides was linked to a 2.4-fold increase in risk and fungicide to a 2.5-fold increase, the researchers say.

It was still not possible to say for definite that insecticide use caused leukaemia and it was unclear what agent in it was potentially dangerous, Menegaux said.

She added: "The consistency of our results and the results from previous studies suggests that it may be opportune to consider preventative action."

Childhood leukaemia linked with household insecticides

Tue, 17 Jan 2006 18:54:00 PST

( from http://www.rxpgnews.com ) Household insecticides may increase the risk of childhood leukaemia, suggests French research in Occupational and Environmental Medicine .

Leukaemia is the most common childhood cancer in France, affecting 43 in every million children every year.

The findings are based on 280 children newly diagnosed with acute leukaemia and a further 288 children matched for sex and age, but free of the disease.

Detailed face to face interviews were carried out with each of their mothers. These included questions about the employment history of both parents, the use of insecticides in the home and garden, and the use of insecticidal shampoos to eradicate head lice.

The risk of developing acute leukaemia was almost twice as likely in children whose mothers said that they had used insecticides in the home while pregnant and long after the birth.

Exposure to garden insecticides and fungicides as a child was associated with a more than doubling of the risk of acute childhood leukaemia. And the use of insecticidal shampoos to eradicate head lice, based on what the mothers had said, was associated with almost double the risk.

The authors say that no one agent can be singled out and a causal relation between insecticides and the development of acute childhood leukaemia "remains questionable,"

They add: "However, the consistency of our results and the results from previous studies suggests that it may be opportune to consider preventive action."

The cure rate for ALL could reach 90 percent

Thu, 12 Jan 2006 05:21:00 PST

( from http://www.rxpgnews.com ) The cure rate for the once almost universally fatal childhood cancer acute lymphoblastic leukemia (ALL) could reach 90 percent in the near future, thanks to improvements in diagnosis and treatment over the past four decades, according to investigators at St. Jude Children's Research Hospital. Almost 4,000 cases of ALL are diagnosed in the United States each year, about two-thirds of which are in children and adolescents, making this disease the most common cancer in this age group.

A report on the progress in the treatment of ALL authored by two St. Jude investigators appears in the January 12 issue of the New England Journal of Medicine.

The progressive improvement in the cure rate since 1962, when only 4 percent of children with ALL survived, reflects in large part the more effective use of existing drugs and the incorporation of sophisticated genetic technologies to personalize treatments, the authors said. Research findings at St. Jude have enabled clinicians to identify patients for whom standard treatment is most likely to fail, and who should therefore be treated more aggressively; these findings have also allowed clinicians to choose the optimal drugs and drug dosages for individual patients.

The improvements in ALL treatment are also helping to reduce the long-term toxic side effects of therapy by enabling clinicians to reduce or avoid the use of certain drugs or radiation that can damage major organs or cause secondary cancers.

"Our success reflects many years of dedication and research by an experienced team that have paid off substantially," said Ching-Hon Pui, M.D., director of the Leukemia/Lymphoma Division at St. Jude and American Cancer Society F.M. Kirby Clinical Research Professor. "A 90 percent cure rate for ALL is quite possible in the near future if we continue to incorporate the breakthroughs of past decades and successfully overcome the remaining challenges."

The dramatic increase in cure rates for children is especially significant in the case of African-American children, Pui noted. They still have poor outcomes in national studies, but studies at St. Jude have shown African-American children have the same high cure rates as white children when given access to the same effective treatments.

"This reflects the ability of St. Jude to provide free treatment to all children regardless of their ethnic or racial backgrounds or their ability to pay; and to tailor the treatment according to their specific needs," Pui said. "The significant leadership role St. Jude played is due entirely to the enormous contributions made by our extraordinary team of doctors, pharmacists, nurses, and other clinicians and scientists over the years," said William E. Evans, Pharm.D., director and chief executive officer of St. Jude and the paper's co-author. "Their efforts are directly responsible for helping to push up the cure rate for ALL.

"Thanks to their work and the work of other institutions, we can now identify factors putting patients at high risk; and that has enabled us to determine whether treatment failure is due to resistance of leukemic cells to drugs, or merely due to the use of inadequate doses of those agents," Evans said. "By having the tools to precisely assess the risk of relapse in a specific patient, we can design the most effective treatments possible at the start of therapy. That's a key element of our success in raising the cure rate for ALL while limiting toxic effects of therapy."

That success is based to a large extent on the work done at St. Jude and elsewhere in identifying specific mutations in leukemic cells that strongly suggest the likelihood that treatment will fail the child, the authors reported. For example, a chromosomal abnormality called the TEL-AML1 fusion gene, which is an abnormal combination of two separate genes, confers a relatively favorable outlook for patients with this form of ALL. But patients whose leukemic cells have another genetic abnormality called the Philadelphia chromosome or a very low number of chromosomes--hypodiploidy--are at increased risk of treatment failure.

Adding to the complexity of the patient's response to treatment are differences in how quickly the body activates, breaks down or eliminates specific cancer drugs.

"Many genetic factors likely interact to influence the response of the patient to treatment," Evans said. "That's why the breakthroughs in pharmacogenomics made at St. Jude and elsewhere are so important. They let clinicians identify the patterns of gene activity and inactivity in both the patient's body and in leukemic cells that influence drug efficacy and toxicity. Without such information we would still be treating ALL using a lot of guesswork instead of good science."

Pharmacogenomics is the study of the effects of different genes on the response to drugs. Such studies often include the analysis of the roles of hundreds or even thousands of genes.

Another significant contribution made by St. Jude researchers is the measurement of minimal residual disease (MRD)--the small populations of leukemic cells that survive initial treatment (induction therapy). These cells can replenish the population of leukemic cells and cause the patient to relapse.

Using highly sensitive techniques, St. Jude researchers developed a technique for identifying abnormal combinations of proteins that appear only on the surface of leukemic cells. This allows scientists to quickly and accurately determine the percentage of such cells in samples taken from the patient. Doctors measure MRD to determine if induction therapy has eliminated enough leukemic cells to ensure a high probability of success. Until now, researchers had to rely on the less-accurate technique of microscopic examination to determine which cells in a child's blood sample were leukemic.

"MRD measurements help us to predict the ultimate response of each patient to treatment," Pui said. "That information helps us to determine how intensive the rest of the therapy should be. Our goal is the complete eradication of leukemic cells with the least toxicity to the children."

The continued improvement in diagnosis and treatment made possible by MRD, pharmacogenomics and new drug therapies has shifted the focus in ALL therapy toward reduction of both the immediate and long-term side effects of treatment. For example, a St. Jude team lead by Evans demonstrated that patients who lack the enzyme TPMT are more sensitive to thiopurine chemotherapy drugs and are more likely to suffer damage to the body's blood-producing cells. Evans subsequently discovered the genetic cause and developed a gene-based test that permits clinicians to identify children who should be treated with lower doses of this class of drugs while still receiving full therapeutic benefit. The overall improvements have led to more skilled use of cancer drugs, stem cell transplantation and treatment of ALL that invades the central nervous system, according to Pui.

"We are now testing the feasibility of omitting irradiation for all patients and reserving this treatment for only those children who suffer a relapse," he noted. "Irradiation of the brain can cause second cancers, hormonal disturbances and disruption of intellectual development as the child grows. So our omission of the use of irradiation should further reduce acute and long-term toxic side effects and improve outcome."

Coupled with the successes of the recent past, future treatment improvements promise to continually improve the survival rate of ALL, Evans said. For example, new drugs directed against the proteins made by genes linked to ALL will add to the options for treating this disease.

"Multiple breakthroughs at St. Jude and elsewhere have transformed ALL from a virtual death sentence into a disease that children can increasingly be expected to survive with minimal side effects," Evans said. "Surpassing 90 percent is an important step toward our ultimate quest of curing all children with this disease.

PCBs, Furans May Factor in Risk of Non-Hodgkin Lymphoma

Fri, 02 Dec 2005 20:03:00 PST

( from http://www.rxpgnews.com ) Scientists have found some additional evidence that environmental exposure to polychlorinated biphenyls (PCBs) may be associated with non-Hodgkin lymphoma, according to a study published in the December 1 issue of Cancer Research.

By comparing blood levels of PCBs in 100 pairs of healthy volunteers and non-Hodgkin lymphoma patients, Anneclaire De Roos, Ph.D., assistant professor of epidemiology, Fred Hutchinson Cancer Research Center, and colleagues determined that high levels of three specific molecular forms of PCBs are linked to an increased risk of developing cancer that starts in patients lymph tissue.

The research also disclosed a potential increased risk of non-Hodgkin lymphoma associated with high blood levels of total dibenzofurans. Furans form as a by-product of waste incineration and other industrial processes and are also present in the environment at lower levels than PCBs.

This study strengthens the hypothesis that persistent organochlorines may be associated with risk of lymphoma, said Nathanial Rothman, a researcher in the National Cancer Institutes Division of Cancer Epidemiology and Genetics.

The furans are a new hypothesis, and the PCB findings provide us with some additional evidence, but these studies really need to be replicated broadly with much larger numbers of cases. Also, it is important to follow-up these findings in prospective cohort studies that collect blood samples from people when they are healthy, so that we can measure organochlorine levels before their disease develops.

Incidence of non-Hodgkin lymphoma has risen through-out the last half of the twentieth century, concurrent with the use and environmental dispersion of synthetic PCBs. Although their production has been banned for more than 25 years in the United States due to toxicological concerns, PCBs persist in the environment and remain in humans because they break down slowly.

Though they arent being produced any more we still detect them in the environment, but at lower levels than in the past, Rothman said.

Nonetheless, the presence of PCBs in the environment and even in the blood of humans doesnt mean that these compounds are cancer-causing substances, he cautioned.

There is still a good deal of uncertainty as to whether PCBs are actually causally associated with any cancer in humans, he said.

While their current report adds more evidence about PCBs and cancer, it was not designed to produce the smoking gun evidence that defines the molecular events induced by cellular exposure to PCBs resulting in initiation of cancer. Also, studies of workers with high occupational exposure to PCBs have not detected an excess of lymphoma, adding uncertainty to the relationship.

We believe our findings could provide an important clue to the cause of NHL, Rothman said. However, these associations need to be examined in other studies. If the relationship is consistently replicated, we need to carefully address whether or not PCBs or furans are likely to cause lymphoma, or if another risk factor that is associated with these chemicals could be the true causative agent.

Nearly 54,000 Americans will be diagnosed with non-Hodgkin lymphoma this year, according to the American Cancer Society. More than 19,000 will die from the disease. More men (23 of every 100,000) develop the lymphatic system cancer than women (16 per 100,000). Most non-Hodgkin lymphoma patients are mature adults. The average age at diagnosis is 60 years, with the average survival of patients with low-grade lymphomas about six to eight years after diagnosis. Some 30 percent of patients diagnosed with high-grade lymphomas are permanently cured after treatment, which varies by type of lymphoma and response to chemotherapies.

Test Vaccine Effective for Follicular Lymphoma

Fri, 11 Nov 2005 00:58:00 PST

( from http://www.rxpgnews.com ) A team of researchers has demonstrated the clinical efficacy and benefits of a vaccine for a type of blood cancer, follicular lymphoma, amongst first time relapse patients. Specialists from two University of Navarre centres the University Hospital and the Research Centre for Applied Medicine (CIMA) - have worked jointly since 2001 on the research. According to Dr. Maurizio Bendandi, the team leader, it is the first time that a vaccine against a type of cancer has been able to change the history of the illness. In Spain more than 5000 persons over 40 are annually diagnosed with this type of cancer. Follicular lymphoma is a tumour of the lymphatic system the cells of which present a surface protein in fact, an immunoglobuline - that can be used as a target. The vaccine, known as idiotypical, is produced from this protein and its aim is to provoke a reaction from the immune system of the patient. Normally the patient does not react against the protein of the tumour given that, as it is a known element, its immune system does not combat it. By means of laboratory techniques we have managed to adhere to the target protein another protein called KLH, obtained from a mollusc. In this way we managed to get the tumoural protein also to be recognised as foreign.

In the case of follicular lymphoma, this protein is a specific tumour antigen. It is postulated that there are also antigens in other tumours but, for the moment, none has been identified solely and exclusively in the tumour cells and, thus, a vaccine against these would also be damaging to healthy tissues.

Stanford University developed an idiotypical vaccine in the seventies in animals and applied it to humans 15 years ago. In 1992 its biological efficacy was tested: it is capable of stimulating the human immune system. In 1999 Dr. Bendandi and other scientists at the US National Cancer Institute demonstrated that this biological efficacy was also clinical. According to the University of Navarre researcher, the vaccine-stimulated immune system itself is capable of killing some tumour cells that had resisted quimiotherapy. It remains to be demonstrated that this result provides a real benefit to the patient.

With the research work carried out at CIMA and the University Hospital it is known that 50% of the patients treated with quimiotherapy relapse within13 months. Moreover, the duration of the response time tends to be shorter between relapses than between the previous ones.

The research involved 25 patients over the last four and a half years. Of these, 4 patients did not respond to the vaccine and relapsed in the expected time, with another 3 the study of their illness is yet to finish and 18 responded satisfactorily. None of these 18 has relapsed over the two years vaccination.

This is the first study of this kind or design to investigate the efficacy of the vaccine in patients suffering relapse, although other clinical trials are being undertaken at two centres in the United States.

The vaccine, administered subcutaneously, is especially useful as a complement to quimiotherapy. There have been attempts to apply the vaccine as a first treatment but the results have not been satisfactory.

In general terms, the procedure followed with patients at the University Hospital was to give them conventional quimiotherapy for 6 months in order to reduce the size of the tumour as much as possible. This was followed by a rest period of between 3 and 6 months in order to reconstitute the immune system. Finally, the vaccine was innoculated every month for three or four months, whereupon the frequency of this dosage was gradually reduced.

Treatment advances for follicular lymphoma have reduced deaths by 70%

Fri, 21 Oct 2005 23:22:00 PST

( from http://www.rxpgnews.com ) New treatment advances for patients with follicular lymphoma, previously considered an incurable cancer, have reduced deaths in the first four years by 70 percent. A newly published study recommends that doctors carefully choose their patients' initial therapies because there are significant differences in overall survival rates, according to researchers at the University of Rochester Medical Center's James P. Wilmot Cancer Center.

Scientists compared outcomes for 960 patients treated with three different regimens; survival rates vary from 91 percent for the newest treatments, which include monoclonal antibodies, to 69 percent for standard therapy.

"This is real evidence that the clinical advances we've made over the last 30 years are prolonging lives," said Richard I. Fisher, M.D., director of the Wilmot Cancer Center and lead author on a paper published online by the Journal of Clinical Oncology. "Some of the new therapies that include monoclonal antibodies have revolutionized treatment of this disease."

Follicular lymphoma, a slow-growing cancer of the lymphatic system, affects about 30,000 older adults each year in the U.S. Median survival has been seven to 10 years, but until this study, there was no evidence of any recent improvements.

Fisher and colleagues from the Southwest Oncology Group, Fred Hutchinson Cancer Research Center in Seattle and University of Arizona Cancer Center assessed three common therapies that have been used over the last two decades.

In the head-to-head comparison, they found that a combination of the standard therapy (a four-drug combination called CHOP, which stands for cyclophosphamide, doxorubicin, vincristine and prednisone) plus new monoclonal antibodies (rituximab or iodine-131 tositumomab) offers the best survival rate during the first four years. The team studied 179 patients who were treated with this regimen during the late 1990s, and the survival rate was 91 percent.

In the second arm of the study, the 425 patients treated during the 1980s with ProMACE-MOPP, an eight-drug, combo-chemotherapy regimen, had a 79-percent survival rate at the four-year point.

The third group of 356 patients received CHOP plus immunostimulant therapies during the 1970s; their four-year survival rate was 69 percent.

"This data gives doctors and patients real evidence that initial treatment decisions have significant impact on the length of survival," Fisher said.

Fisher has studied CHOP therapy and other combinations with the Southwest Oncology Group, one of the largest research cooperative groups, for the last three decades. He has led studies that demonstrated its effectiveness as a treatment for aggressive lymphomas.

Risk of Lymphoma Higher Among People With Family History of Hematopoietic Malignancy

Wed, 05 Oct 2005 04:17:00 PST

( from http://www.rxpgnews.com ) A new study has confirmed the association between family history of hematopoietic malignancy--cancers of the blood or bone marrow, such as leukemia and lymphoma--and the most common types of lymphoma.

Because a family history of hematopoietic malignancy is associated with an increased risk of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma but the magnitude of the risk is unclear, Ellen T. Chang, Sc.D., of the Karolinska Institute in Stockholm, Sweden, and colleagues estimated the association between familial hematopoietic cancer and risk of lymphoma using validated family data from the Swedish Multi-Generation Register and Cancer Register.

They found that a history of hematopoietic malignancy in any first-degree relative was associated with an approximately two-fold increased risk of all NHL, common B-cell NHL subtypes, and Hodgkin lymphoma. The associations between certain environmental factors and lymphoma risk did not vary between individuals with and without familial hematopoietic malignancy.

New blood transplant method stops fatal side effect

Thu, 29 Sep 2005 20:35:00 PST

( from http://www.rxpgnews.com ) Findings published in the Sept. 29 issue of the New England Journal of Medicine suggest that the new therapy pioneered at Stanford University School of Medicine has paid off for lymphoma and leukemia patients. Marty Holmes, a landscaper from Stockton, Calif., became the 40th person to undergo this procedure after Stanford researchers had shown that it could boost the relative levels of regulatory T cells in the immune system of mice - an effect that turned out to be beneficial before undergoing a hematopoietic (blood) stem cell transplantation, a common treatment for blood cancers.

Blood stem cell transplantation replaces the cancerous blood cells of a leukemia or lymphoma patient with those from a healthy donor. The transplantation cures the cancer, but in up to 80 percent of the cases there is a potentially deadly side effect: The donor's incoming immune cells attack the patient's body as "foreign" in what is known as graft-versus-host disease.

The new method tested at Stanford appears to retain the desired result of the transplantation - killing the cancerous cells - without inducing the acute form of graft-versus-host disease. "It allows you to throw out the one effect but not the other," said Samuel Strober, MD, professor of medicine (immunology and rheumatology) and the senior author of the study.

Among the 37 study participants included in the National Institutes of Health-funded clinical trial, there was more than a tenfold reduction in the incidence of acute graft-versus-host disease. Only 5 percent, or just two patients, experienced the acute form of the disease.

"You would have expected something in the order of 30 to 60 percent incidence of severe graft-versus-host disease in these patients, according to conventional methods," said Strober. "And it didn't look like there was a price to be paid for this major reduction," he added, explaining that the patients did not have any higher rate of infections or relapse.

The majority of patients who were in partial remission went into complete remission, and those who were in complete remission didn't relapse over the course of the three-year study.

The treatment was not as effective in stemming the less-serious, chronic form of graft-versus-host disease. The study found no apparent difference in the typical rates of the chronic form of the condition among the patients who survived more than 100 days after transplantation.

Acute graft-versus-host disease occurs within 100 days of transplantation and involves the donor immune cells attacking the host's skin, intestines and liver. It is lethal in up to 40 percent of the cases. Chronic graft-versus-host disease is characterized by such long-term problems as dryness of the eyes and mouth, skin rashes, stiff joints, weight loss caused by intestinal scarring, and more infections due to a weakened immune system.

"We didn't seem to impact much on the incidence of chronic graft-versus-host disease, maybe a bit," said the paper's first author, Stanford assistant professor of medicine Robert Lowsky, MD. "With the acute form we did wonders, and acute is often the more worrisome complication."

Robertson Parkman, MD, an immunologist who was not involved in the study, said that the new procedure "is definitely a significant improvement" over the existing methods. He did, however, find it a bit problematic that the patients continue to show some chronic graft-versus-host disease. "Reducing acute graft-versus-host disease is a good thing, but this approach may not be as much of a total panacea as we'd like it to be," said Parkman, professor of pediatrics in the Division of Research Immunology/Bone Marrow Transplant at Children's Hospital Los Angeles.

The Stanford researchers said that more research is needed, and they hope to begin testing their method with other cancer centers soon.

It makes sense that the regulatory T cells - a tiny subset of immune cells - could play such a vital role in stemming graft-versus-host disease: These cells appear to act as the immune system's peacekeepers, signaling to other immune cells to hold off from attacking an intruder. Thus, it seemed promising to use them to stop the newly transplanted cells from attacking the host.

Strober has studied regulatory T cells for more than 25 years. He weathered through a time when many immunologists doubted that regulatory (formerly called suppressor) T cells even existed. Through the years, he fine-tuned a method to harness the elusive cells' immune system-soothing abilities in mice. Using a combination of irradiation and antibodies, he was able to preferentially boost the mice's regulatory T cells from about 1 percent of the total T cells to more than 90 percent. The treated mice had a dramatic reduction in acute graft-versus-host disease compared with untreated mice following a blood stem cell transplantation.

But would the strategy be as successful in humans? To find out, he teamed up with Lowsky, who had experience trying novel strategies for improving blood stem cell transplantations as director of the blood and marrow transplantation program of the Saskatchewan Cancer Agency until moving to Stanford in 2001. Together, Lowsky and Strober modified the mouse protocol to be used in humans.

"The beauty of this study is that it is a practical example of translating an animal model to the clinic," said Lowsky.

MicroRNA genes are involved in CLL development

Tue, 13 Sep 2005 04:52:00 PST

( from http://www.rxpgnews.com ) A new and unusual class of genes plays an important role in the development of chronic lymphocytic leukemia (CLL), according to new research here. At the same time, these genes may provide a new form of therapy for the disease.

CLL strikes some 9,700 Americans annually, making it the most common adult leukemia in the world.

The study found that the loss of two genes for producing small molecules known as microRNAs enables damaged cells to survive, rather than normally self-destructing before they become cancerous.

Our findings show that microRNA genes are involved in the development of CLL, says principal investigator Carlo M. Croce, professor and chair, Department of Molecular Virology, Immunology and Medical Genetics at Ohio State, and director of the Human Cancer Genetics Program at the OSU Comprehensive Cancer Center. They also strongly suggest that microRNAs might be used therapeutically for CLL and probably other cancers.

The research is published online in the current issue of the Proceedings of the National Academy of Science.

The two microRNA genes are known as miR-15 and miR-16. Earlier work led by Croce showed that about 65 percent of CLL patients have cancer cells that show the loss of, or damage to, these genes.

This study shows that the two microRNAs interact closely with a protein known as Bcl-2. That protein stops cells from self-destructing through a natural process known as apoptosis. (In 1984, Croce led the research that discovered the Bcl-2 gene.)

In CLL cells and cells from other kinds of cancer, the Bcl-2 protein is present in abnormally high levels. This prevents the malignant cells from self-destructing as they should and leads to tumor growth. In about 95 percent of CLL cases, scientists did not know why Bcl-2 was present at high levels. The current paper now answers that.

Croce and his colleagues discovered that the miR-15 and miR-16 microRNAs play an important role in controlling Bcl-2 levels, normally keeping them low. When the two microRNA genes are lost as often happens in CLL the levels of Bcl-2 rise, the cells do not self-destruct as they should, allowing cancer to occur.

Croce and his colleagues explored the relationship between miR-15 and miR-16 in several experiments.

For example, the investigators compared cells from 26 CLL patients with cells from four healthy individuals. The normal cells showed high levels of the two microRNAs and low levels of the Bcl-2 protein; the CLL cells showed just the opposite: low levels of the two microRNAs and high levels of the Bcl-2 protein.

In another experiment, the researchers used laboratory-grown leukemia cells that had lost the two microRNAs. These cells showed high levels of Bcl-2.

Perhaps most importantly, when the researchers then put genes for miR-15 and miR-16 into the cells, the levels of the Bcl-2 dropped and the cells began to self-destruct through apoptosis.

This finding is significant, and it also suggests that miR-15 and miR-16 provide an effective therapy for tumors that overexpress Bcl-2, Croce says. It also suggests that the loss of miR-15 and miR-16, and the resulting over-expression of Bcl-2, is the main mechanism of human CLL development in a major fraction of cases.

Tositumomab Brings New Hope for Refractory Non-Hodgkin's Lymphoma

Sat, 10 Sep 2005 23:02:00 PST

( from http://www.rxpgnews.com ) Health Canada has approved a new treatment that could offer hope for those who suffer from what is considered an incurable form of non-Hodgkin's lymphoma (NHL) and who have failed on, or relapsed following, other treatments. Health Canada approved Bexxar(TM) (tositumomab and iodine I 131 tositumomab) therapy for the treatment of patients with CD20 positive relapsed or refractory, low grade, follicular, or transformed non-Hodgkin's lymphoma, including patients with rituximab- refractory NHL.

"Bexxar represents an important new direction in cancer therapy," says Dr. Harold J. Olney, hematologist, medical oncologist and principal investigator for Bexxar's current Canadian clinical trial. "Bexxar is an NHL treatment that is tailored to administer a targeted and patient-specific therapeutic dose of radiation, thereby preventing either under or overdosing of radiation. For patients who have not responded or have relapsed following front line treatments, Bexxar is an important and welcome option."

Bexxar is the latest of a new generation of patient-tailored cancer treatments that specifically targets non-Hodgkin's lymphoma cells, while minimizing risk to surrounding healthy cells. Bexxar is given at a dose specific to individual patient characteristics, usually in an outpatient setting. Administered in a short treatment course, Bexxar can provide long- lasting responses in patients whose disease has not responded to other treatments. In clinical studies, approximately one in four patients on Bexxar were shown to have a durable complete response of greater than one year.

Bexxar was granted Health Canada's Priority Review status, which is reserved for new drugs that have the potential ability to address serious, life-threatening or severely debilitating illness or conditions for which there is an unmet medical need. Bexxar is expected to be available in Canada in October, 2005.

About Bexxar Therapy

Bexxar is a dual-action therapy that pairs the tumor-targeting ability of a cytotoxic (cancer killing) monoclonal antibody (tositumomab) and the therapeutic effect of patient-specific radiation (iodine-131) dosing. Antibodies (tositumomab) target and attach to cancer cells deep inside the tumor (antigen CD20 found on NHL cells). The radiation dose (iodine 131) then targets tumors with minimal risk to surrounding healthy cells.

Clinical Study Results

The efficacy of Bexxar therapy was examined in a multi-center, single-arm study of 40 patients with follicular NHL whose disease had relapsed following or had not responded to rituximab. The median age of patients in the study was 57 (range: 35-78) and the median number of prior chemotherapies was four (range: 1-11). Eighty-eight per cent of patients met the definition of rituximab refractory (defined as no response or a response of less than six months in duration). In these patients with rituximab refractory disease, 63 per cent of patients had a response to Bexxar, with a median duration of response of 25 months. Twenty-nine per cent of these patients had a complete response (no clinical signs of disease) to Bexxar. The median duration of complete responses had not been reached after a median follow up of 26 months.

The results of this study were supported by demonstration of durable objective responses (lasting more than one year) in one phase III and three other single-arm studies, enrolling 190 patients with rituximab-naive, follicular NHL, with or without transformation, who had relapsed following or were refractory to chemotherapy. In these studies, the overall response rates ranged from 47 per cent to 64 per cent and the median durations of response ranged from 12 to 18 months.

Side Effects

The most common adverse reactions occurring in the clinical trials included neutropenia, thrombocytopenia and anemia. Less common but severe reactions included pneumonia, pleural effusion and dehydration.

The most common non-hematologic side effects included asthenia (weakness), fever, nausea, infection and cough. Bexxar was associated with a risk of hypothyroidism and human anti-murine antibody (HAMA) formation. Certain chemotherapy agents and ionizing radiation have been associated with the development of myelodysplasia (MDS), secondary leukemia and solid tumors. MDS, secondary leukemia and solid tumors have also been observed in patients receiving Bexxar therapy.

Administration of Bexxar may result in infusion-related reactions that may be induced by the administration of foreign proteins. Hypersensitivity reactions occurred in six per cent of patients. Adjustments of the rate of infusion to control adverse reactions were required in seven per cent of patients.

Bexxar Therapy

Bexxar consists of four components administered in two steps over seven to fourteen days, usually on an outpatient basis. The first set of infusions includes the non-radioactive antibody, tositumomab, used to improve the distribution in the body of the subsequent radioactive antibody and increase its uptake in the tumor, followed by a dosimetric infusion, containing the antibody and a trace amount of radioactive iodine 131. This dosimetric step allows for visualization of the location of the radioisotope and the determination of the rate of clearance of radioactivity from the body by the use of gamma camera counts obtained at three time points. Clearance is dependent on factors such as tumor size and bone marrow involvement. From these determinations, the patient-specific amount of radioactivity necessary to deliver the targeted therapeutic total body dose of radiation can be calculated. Seven to fourteen days after the dosimetric step, the patient returns for the therapeutic step, which again includes two infusions, beginning with the non-radioactive antibody, but this time followed by the calculated patient-specific radioactivity needed to deliver the targeted total body dose of radiation.

About non-Hodgkin's Lymphoma

Non-Hodgkin's lymphoma is a form of cancer that affects the blood, bone marrow and lymphatic tissues. Unlike most major forms of cancer, both incidence and mortality rates of NHL are increasing. Incidence rates for NHL in Canada have more than doubled over the last thirty years and are among the highest in the world.(1) The Canadian Cancer Society estimates that 6,400 new cases will be diagnosed in 2005 and that 3,000 Canadians will die this year from the disease(2). Transformed non-Hodgkin's lymphoma can be an aggressive and difficult to treat form of follicular non-Hodgkin's lymphoma with a particularly poor prognosis.

AMD-3100 May Help Cancer Patients in Need of Stem Cell Transplants

Fri, 09 Sep 2005 15:54:00 PST

( from http://www.rxpgnews.com ) A new drug may help cancer patients mobilize the cells necessary to restore their blood-forming system after high-dose chemotherapy, according to results from a clinical trial at the Kimmel Cancer Center at Thomas Jefferson University Hospital in Philadelphia and at other centers across the nation.

In the phase II trial, researchers were attempting to determine if patients with multiple myeloma or non-Hodgkins lymphoma who received the drug AMD-3100 along with the standard drug G-CSF (granulocyte-colony stimulating factor) would have more stem cells available for transplantation.

AMD-3100 blocks a specific cellular receptor, triggering the movement of stem cells out of the bone marrow and into the circulating blood, boosting the supply of marrow stem cells available for transplantation. Stem cell transplantation entails collecting certain types of cells known as hematopoietic stem cells from patients who receive treatment with high-dose radiation and/or chemotherapy for cancers such as leukemias, lymphomas and multiple myeloma, all of which involve the blood and immune system. The cells, once returned to the body, help restore the blood-forming system within the bone marrow and the bodys immune system, which is severely damaged if not destroyed by treatment.

Stem cell transplantation is considered front-line therapy for multiple myeloma, or cancer of the bone marrow, and for high-risk leukemia and lymphoma patients, says Neal Flomenberg, M.D., professor of medicine and director of medical oncology at Jefferson Medical College of Thomas Jefferson University, who led the trial at Jefferson.

The researchers found that all of the 25 patients (10 patients with multiple myeloma and 15 patients with non-Hodgkins lymphoma) given the drug combination could move enough cells from the marrow to the bloodstream compared to only 64 percent of those who had G-CSF alone. They report their results September 1, 2005 in the journal Blood.

As a result, Dr. Flomenberg says, there were fewer stem cell collections necessary and more stem cells retrieved. The greater the number of available stem cells, the more likely transplantation will be successful. In some cases, this can mean the difference between a patient being able to receive a transplant or not. The drug has little toxicity.

One of the most important results from the trial was that nine patients who would not have been able to mobilize stem cells to go to transplant with G-CSF alone could now mobilize them with the combination of G-CSF and AMD-3100, Dr. Flomenberg says.

In addition, some patients who received AMD-3100 needed fewer stem cell collections to get the necessary number of cells, making the overall process less taxing. Those who still required the same number of collections had a higher total of stem cells.

Its hoped that the drug combination will make white cell and platelet recovery quicker and allow patients who wouldnt have otherwise been able to mobilize stem cells for transplant now be able to do so, he says. Without adequate numbers of stem cells for transplantation, patients may have a delayed recovery of their immune systems and be at greater risk of infection.

Most patients undergo standard chemotherapy for four to eight months before they have a stem cell transplant, he explains. Some patients wont have a transplant until their disease relapses and treatment once again puts them back in remission. These treatments sometimes make subsequent stem cell collection difficult.

Approximately 25 percent to 35 percent of transplant patients and perhaps as many as 65 percent have trouble moving optimal numbers of stem cells from their bone marrow into the bloodstream using G-CSF. Some patients with the standard approach dont mobilize well, meaning more collections and often a poor or unusable cell product, he says.

Dr. Flomenberg believes that the drug combination will become a standard treatment for such cases involving stem cell transplantation. The treatment has potential to alter the standard of practice, he says.

Researchers currently are conducting two phase III trials comparing G-CSF and placebo to G-CSF and AMD-3100 in 600 patients with either non-Hodgkins lymphoma or multiple myeloma, he notes. Jefferson is participating in both trials, in addition to another phase II trial with AMD-3100 alone.

Lenalidomide & dexamethasone combination shows promise for multiple myeloma treatment

Sun, 04 Sep 2005 07:16:00 PST

( from http://www.rxpgnews.com ) Mayo Clinic Cancer Center investigators report that combination therapy with lenalidomide (RevlimidTM) and dexamethasone (combination is called Rev/Dex) looks like a breakthrough treatment for multiple myeloma. Results of a Phase II clinical trial were published online Aug. 23 in Blood.

"Previous studies have shown Rev/Dex to be effective for recurrent or highly resistant forms of myeloma," says S. Vincent Rajkumar, M.D., Mayo Clinic hematological oncologist and lead investigator of the study, "In this study, the first one to use the combination as initial therapy in newly diagnosed patients, we find that the Rev/Dex combination reduced the myeloma cancer protein levels by more than half in 91 percent of patients much higher than response rates obtained with current approved therapies."

The goal of this clinical trial was to determine the response rate and toxicity (type and severity of side effects) of Rev/Dex in patients with previously untreated, newly diagnosed multiple myeloma. Over the course of the trial, 34 patients underwent the combination treatment, with 31 (91 percent) showing positive response to the treatment, and all within a rapid period average response time was one month. In addition to the quick and positive responses, side effects were manageable, and common ones associated with thalidomide treatment, such as constipation, blood clots and neuropathy, were uncommon. Rev/Dex is administered orally making it a more attractive option to many patients compared to traditional intravenous treatments.

"We see this as potentially the way of the future for many myeloma patients," says Morie Gertz, M.D., Mayo hematological oncologist and co-investigator, "We are happy that two large Phase III trials are currently ongoing, moving forward the testing of Rev/Dex as initial therapy for myeloma."

Multiple myeloma is a malignant cancer of the blood that causes 11,000 deaths each year. Standard therapy of melphalan and prednisone results in about 50 percent of patients having a positive response i.e. the cancer cells lessen by more than half. Vincristine, doxorubicin and dexamethasone (VAD) is another chemotherapy regimen used to treat myeloma, typically for patients who are candidates for stem cell transplantation because it allows adequate and safe stem cell harvest during treatment for a future transplantation. However, the use of VAD chemotherapy has decreased greatly because of the need for intravenous therapy and the need for a catheter bringing other potential health risks.

Recent studies have looked at the oral combination of thalidomide and dexamethasone (Thal/Dex) as an alternative to VAD. Although response rates are excellent (approximately 70 percent), the combination causes significant side effects. Lenalidomide is a compound similar to thalidomide, but one which previous studies have shown to work better both for recurrent and highly resistant myelomas, both alone and in conjunction with dexamethasone. It has fewer side effects than thalidomide and has even caused improvement in patients who are nonresponsive to thalidomide.

Lenalidomide is not commercially available; approval by the Food and Drug Administration is pending. The study was funded with grants from the National Cancer Institute and Celgene Corporation, which manufactures RevlimidTM.

Viral protein vFLIP K13 of HHV8 appear to cause lymphoma

Tue, 23 Aug 2005 20:22:00 PST

( from http://www.rxpgnews.com ) A protein previously thought to merely hinder the activity of a key cellular protein linked to cancer cell death, now appears to mimic the cellular signaling of that protein; potentially leading to the development of lymphoma. The findings, published in the Aug. 22 online edition of Proceedings of the National Academy of Sciences (PNAS), demonstrate that a viral protein associated with human herpesvirus 8, or HHV8, may help to cause lymphoma by activating a key pathway involved in the production of lymphocytes, a common cell type found in lymphoid tissue that divide over and over and eventually develop into lymphoma.

The protein, called vFLIP K13, had been thought to protect virally infected cells from attack by the body's own immune system by inhibiting the activity of a cellular protein called caspase 8 that is associated with apoptosis, or programmed cell death. However, when Preet M. Chaudhary, M.D., Ph.D., senior author of the study and professor of medicine at the University of Pittsburgh School of Medicine, and his colleagues analyzed transgenic mice expressing vFLIP K13, they found that vFLIP K13 failed to block cell death pathways and instead mimicked a recently discovered signaling function of caspase 8, which led to the proliferation of lymphocytes.

Dr. Chaudhary and his colleagues observed tumor formation in 59 mice over the course of 30 months. They found that the vFLIP-expressing transgenic mice had more lymphomas than the control group mice; 11.8 percent compared 1.8 percent, respectively.

"We were surprised to see that the mouse model we developed based on vFLIP K13 did not look like the other models in which caspase 8 function was inhibited," said Dr. Chaudhary. "It indicated to us that the main function of this protein is not to block caspase 8 activation."

Further analysis also revealed that instead of inhibiting caspase 8, vFLIP K13 copied its signaling activity resulting in the activation of a distinct cellular pathway called NF-?B that is involved in the development of lymphoma. "In effect, vFLIP K13 actively promoted the growth of cancer cells through this pathway. Based on these findings, we believe the NF-?B pathway may be a promising target for novel therapies directed against HHV8-associated tumors," said Dr. Chaudhary. He added that there is a dire need for new therapies that target this disease since most patients with HHV8-associated lymphomas are highly immune suppressed and are difficult to treat given the toxicity associated with conventional therapies.

In addition to its role in the development of HHV8-associated cancers, the NF-?B pathway also may be implicated in lymphomas that are not caused by HHV8. "There are potentially widespread applications of this finding and our next step will be to discover how involved this pathway is in the development of lymphomas that are not associated with HHV8," said Dr. Chaudhary.

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. They begin with the malignant transformation of a lymphocyte in the lymphatic system. The American Cancer Society estimates that 63,740 people in the U.S. will be newly diagnosed with lymphoma by the end of 2005.

HHV8, originally linked to Kaposi's sarcoma the most common cancer among AIDS patients also is associated with lymphoid diseases such as primary effusion lymphoma and multicentric Castleman's disease, a noncancerous but severe disorder characterized by enlargement of the lymph nodes. Recent studies have also linked HHV8 infection to HIV-related solid immunoblastic/plasmablastic lymphomas.

People who drink alcohol have a lower risk of non-Hodgkin's lymphoma (NHL)

Mon, 15 Aug 2005 20:26:00 PST

( from http://www.rxpgnews.com ) People who drink alcohol have a lower risk of non-Hodgkin's lymphoma (NHL) than non-drinkers, researchers at Yale's Department of Epidemiology and Public Health (EPH) write in an article published in Lancet Oncology.

Led by former EPH graduate student Lindsay M. Morton of the National Cancer Institute, the research team found that the protective effect of alcohol did not vary by type of alcohol consumed, and did not increase along with alcohol consumption. However, the protective effect of alcohol did vary by NHL subtype, and was greatest for Burkitt's lymphoma. Age, sex, family history of NHL, and history of cigarette smoking did not reduce the effect of alcohol consumption on NHL risk.

The findings come at a time when NHL incidence is rising throughout the world. In developed countries, NHL is the sixth most common cancer in men and the eighth most common in women. Previous studies examining the relationship between alcohol consumption and NHL risk have been inconsistent, likely due to small sample size resulting from stratification by NHL subtype and type of alcohol consumed.

"This study with a large sample size allows us with sufficient statistical power to analyze the data by type of alcohol consumed and disease subtype," said principal investigator Tongzhang Zheng, associate professor of epidemiology at EPH. "The resulting study was a pooled analysis of original data from nine case-control studies in the International Lymphoma Epidemiology Consortium (InterLymph), with a pooled study population of 15,175."

Susan T. Mayne, a nutrition epidemiologist at EPH and an author on the study said that further studies are needed to confirm the findings and to determine whether certain lifestyle factors or alcohol's immunomodulatory effects explain the association between alcohol consumption and decreased NHL risk.

Other authors on the study included Yale Professor Theodore R. Holford. Authors from other institutions included Elizabeth A. Holly, Brian C.H. Chiu, Adele Seniori Costantini, Emanuele Stagnaro, Eleanor V. Willett, Luigino Dal Maso, Diego Serraino, Ellen T. Chang, Wendy Cozen, Scott Davis, Richard K. Severson, Leslie Bernstein, Fred R. Dee, James R. Cerhan, and Patricia Hartge.

REVLIMID gets Priority Review Status for the Treatment of Myelodysplastic Syndromes

Tue, 21 Jun 2005 21:25:00 PST

( from http://www.rxpgnews.com ) Celgene Corporation announced that the U.S. Food and Drug Administration (FDA) has granted a Priority Review designation to its New Drug Application (NDA) for REVLIMID with a Prescription Drug User Fee Act (PDUFA) date by October 7, 2005. The Company is seeking approval to market REVLIMID as a targeted treatment for transfusion-dependent patients with low- and intermediate-risk myelodysplastic syndromes (MDS) with deletion 5q chromosomal abnormality.

Priority Review is granted to a pharmaceutical product that, if approved, would be a significant improvement compared to existing marketed products or approved therapies in the treatment, diagnosis, or prevention of a disease. It is the expectation of the Company that the application will be reviewed at an Oncology Drug Advisory Committee (ODAC) meeting in September. NDAs with priority review receive expedited treatment, with the target review period for the application reduced from ten months to six months.

The NDA submission was based primarily upon the safety and efficacy results of an open-label, multi-center Phase II study of low- and intermediate-risk myelodysplastic syndromes (MDS) patients with deletion 5q chromosomal abnormality (MDS-003), and supplemented by supportive data from two additional MDS trials. The MDS-003 data were recently presented during a plenary session at the May 2005 meeting of the American Society of Clinical Oncology.

The Celgene clinical and regulatory management team has been further strengthened by the addition of Robert J. DeLap, M.D., Ph.D., as Vice President of Global Medical Research reporting to Jerome B. Zeldis, M.D., Ph.D., Chief Medical Officer and Vice President of Medical Affairs for Celgene. Dr. DeLap has extensive medical and scientific background, and a broad range of experience in academic medicine, pharmaceutical drug development, and regulatory affairs. His prior experience has included several years at the U.S. Food and Drug Administration, where he served as Director of the Division of Oncology Drug Products and later was Director of the Office of Drug Evaluation V in FDA's Center for Drug Evaluation and Research. He has also held senior positions in drug development and regulatory affairs, at other major pharmaceutical companies, and was on the faculty of the Georgetown University School of Medicine.

About REVLIMID(R)

REVLIMID, an IMiD(R) immunomodulatory drug, represents an innovative approach in addressing unmet medical needs in cancer and immune-inflammatory diseases. Celgene currently is evaluating treatments with REVLIMID for a broad range of hematology and oncology conditions, including; multiple myeloma, the malignant blood cell disorders known as myelodysplastic syndromes, chronic lymphocytic leukemia, as well as solid tumor cancers. REVLIMID affects multiple intracellular biological pathways. The pipeline of IMiDs, including REVLIMID, is covered by a comprehensive intellectual property estate of U.S. and foreign issued and pending patent applications including composition-of- matter and use patents.

REVLIMID is not approved by the FDA or any other regulatory agencies as a treatment in any indication and is currently being evaluated in clinical trials for efficacy and safety for future regulatory applications.

About Myelodysplastic Syndromes

Myelodysplastic syndromes are a group of hematologic malignancies that affect approximately 300,000 people worldwide. Myelodysplastic syndromes occur when blood cells remain in an immature or "blast" stage within the bone marrow and never develop into mature cells capable of performing their necessary functions. Eventually, the bone marrow may be filled with blast cells suppressing normal cell development. According to the American Cancer Society, 10,000 to 20,000 new cases of MDS are diagnosed each year in the United States, with mean survival rates ranging from approximately six months to six years for the different classifications of MDS. MDS patients must often rely on blood transfusions to manage symptoms of anemia and fatigue until they develop life-threatening iron overload and/or toxicity, thus underscoring the critical need for new therapies targeting the cause of the condition rather than simply managing its symptoms.

About Deletion 5q Chromosomal Abnormality

Chromosomal (cytogenetic) abnormalities are detected in more than half of patients with myelodysplastic syndromes, and involve a deletion in all or part of one or more specific chromosomes. The most common cytogenetic abnormalities in MDS are deletions in the long arm of chromosomes 5, 7, and 20. Another common abnormality is an extra copy of chromosome 8. A deletion involving the 5q chromosome may be involved in 20 to 30% of all MDS patients. The World Health Organization has also recently identified a unique subset of MDS patients with a "5q- Syndrome" where the only chromosomal abnormality is a specific portion of the 5q chromosome.

VX-680 : An Aurora Kinase Inhibitor Enters an Additional Phase I Study for its Use in Hematologic Cancers

Mon, 20 Jun 2005 10:52:00 PST

( from http://www.rxpgnews.com ) Merck & Co, Inc and Vertex Pharmaceuticals Incorporated announced the initiation of an additional Phase I clinical study with VX-680, a small molecule inhibitor of Aurora kinases. The two-part, open-label, dose escalation study is designed to evaluate the safety and tolerability of VX-680 when administered over a five-day treatment cycle in patients with hematologic cancers.

The study will evaluate VX-680 in patients with relapsed or refractory acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), acute lymphocytic leukemia (ALL) or chronic myelogenous leukemia (CML) in blast crisis. With the start of this clinical study, Merck and Vertex now have three clinical studies underway with VX-680 in cancer.

The initiation of this clinical study is supported by VX-680's activity against hematologic cancers in both in vitro and in vivo studies. VX-680 is a potent inhibitor of Aurora kinases and of Flt-3 kinase, which have been implicated in the onset and progression of human leukemias.

VX-680 has demonstrated prolonged survival and induced sustained remission in a model of human AML, and has also shown profound effects in a number of other preclinical cancer models.

"The biologic profile and preclinical studies of VX-680 indicate that this compound has the potential for treating a broad range of human leukemias by inducing apoptosis in the cells that drive disease," said Stephen H. Friend, M.D., Ph.D., executive vice president, Advanced Technology and Oncology, Merck Research Laboratories. "The clinical study announced today is designed to promote rapid clinical assessment of VX-680 in patients with a variety of leukemic and pre-leukemic disease states. In addition, access to the leukemic cells in the blood provides a unique opportunity for understanding the biologic effects and anti-cancer activity of Aurora kinase inhibition on a molecular level."

VX-680 Clinical Studies

In addition to this Phase I study in hematologic cancers announced today, Merck is presently conducting two clinical studies of VX-680 in patients with recurrent or non-responsive solid tumors, or cancers for which standard therapy does not currently exist.

Background: Aurora Kinases and the VX-680 Collaboration

Cancer cells typically contain mutations in a number of genes, which ultimately result in uncontrolled cell growth and tumor metastasis. As enzymes specific for and essential to cell growth and division, Aurora kinases hold the potential to be important control points for slowing the growth and spread of tumors. Aurora kinases (also known as BTAK and STK15) are a family of serine-threonine kinases that are believed to play multiple roles in the development and progression of cancer by acting as regulators of cell proliferation, by transforming normal cells into cancer cells and by down-regulating p53, one of the body's natural tumor suppressors. Aurora kinases are known to be over-expressed in many tumor types, including colon cancer, breast cancer and leukemia. Amplification of Aurora genes is associated with progression of colorectal cancer and poor prognosis in certain types of breast cancer.

In June 2004, Vertex and Merck entered into a global collaboration to develop and commercialize VX-680. Along with clinical development, Vertex and Merck are conducting a joint research program to characterize VX-680's activity across a broad range of cancer types and will seek to identify additional drug candidates targeting the Aurora kinases.

Genes linked to treatment resistance in leukemia

Sat, 04 Jun 2005 02:07:00 PST

( from http://www.rxpgnews.com ) Today, the most common childhood cancer is cured in about 80 percent of patients; only forty years ago, this number was closer to five percent. In efforts to further increase the survival rate, researchers from St. Jude Children's Research Hospital, the University of Tennessee, and the University of Chicago studied how an individual's genetics might play a role in the effectiveness of chemotherapy drugs. Their findings will be published in the June 15, 2005, issue of Blood, the official journal of the American Society of Hematology.

The researchers studied 246 children with acute lymphoblastic leukemia (ALL), all of whom were assigned to one of two groups that determined the intensity of therapy. Patients with poorer prognostic factors 130 children were assigned to a high-risk group; the remaining children were enrolled in the lower-risk arm.

In a process known as genotyping, DNA was extracted from the normal blood cells of each child and screened for sixteen common genetic variations. The studied genes code for enzymes which are involved in the metabolism and activity of chemotherapy drugs in the body, and were therefore likely to have effects on treatment outcomes.

In the analysis of the high-risk group, the GSTM1 non-null genotype was associated with hematological relapse, a recurrence of the cancer in the blood and bone marrow and the most common reason for treatment failure in childhood ALL. This risk was further increased if the child also had a TYMS 3/3 genotype. No genotype was associated with hematological relapse among patients in the lower-risk arm of the study.

The researchers also looked for evidence of leukemia in each patient's central nervous system (CNS), a region that is vulnerable to infiltration by cancer cells. Genetic variations may have particular impact on how drugs penetrate the "blood-brain" barrier that protects the CNS. For patients in the high-risk arm, the VDR FokI genotype was found to be prognostic for CNS relapse, especially when combined with a VDR intron 8 genotype. In the low-risk group, the TYMS 3/3 genotype was a risk factor.

For children with these unfavorable genotypes, a potential solution may be using drugs that are not affected by these particular enzymes or increasing the dosage of drugs that are. And, in the future, a simple blood test may be all that's needed to make that determination.

"This research showcases a new direction for cancer treatment personalized chemotherapy based on the genetics of the patient," said Mary Relling, Pharm.D., St. Jude faculty member and lead study author. "In our study, several common genetic variations were found to predict the outcomes of leukemia patients, demonstrating that genotyping may become an important tool for tailoring treatment and improving an individual's chance of a cure."

Novel combination overcomes drug-resistant myeloma

Fri, 03 Jun 2005 16:51:00 PST

( from http://www.rxpgnews.com ) A novel strategy devised by Dana-Farber Cancer Institute scientists has proved highly effective in killing drug-resistant multiple myeloma cells in the laboratory and could open a new form of attack on the deadly blood cancer, they report.

Highly encouraged by the findings, the researchers hope to move rapidly to clinical trials of the therapy, a combination of the drug Velcade and an experimental compound that was designed by researchers at the Broad Institute of Massachusetts Institute of Technology and Harvard University.

The report, which will be posted online this week by the Proceedings of the National Academy of Sciences (http://www.pnas.org/papbyrecent.shtml), demonstrates that the combination was more than twice as effective as either drug alone in killing resistant cells from patients' bone marrow.

The promise is particularly exciting, scientists say, because many patients don't respond to Velcade, a drug approved just two years ago that's been an important new therapy for multiple myeloma, a disease which caused an estimated 11,000 deaths in 2004, according to the Multiple Myeloma Research Foundation.

"This is not just another drug, this is a whole new approach to treating multiple myeloma," said Kenneth Anderson, MD, senior author of the paper, whose lead author is Teru Hideshima, MD, also of Dana-Farber. Others include Stuart L. Schreiber, PhD, of Harvard University and the Broad Institute, and Jay Bradner, MD, of Dana-Farber and the Broad Institute.

Velcade is the first in a class of so-called proteasome inhibitors, which cause lethal stress in cancer cells by blocking the proteasome, a disposal mechanism that rids the cell of abnormal proteins. Cells in which the proteasome is jammed eventually commit suicide, triggered by the accumulation of proteins, explains Anderson, who is also the Kraft Family Professor of Medicine at Harvard Medical School.

However, many cancer cells are resistant to proteasome inhibitors like Velcade. Recent studies have revealed an alternative protein-disposal complex, the aggresome, that may take over enough of the job when the proteasome falters to allow the cells to survive.

Therefore, the Dana-Farber researchers suggested that blocking both protein disposals at once might get around this resistance mechanism. Scientists led by Schreiber at the Broad Institute designed a drug, tubacin, that blocks histone deacetylase 6, an enzyme that is critical to the aggresome's ability to function.

These highly promising results, wrote the researchers, "provide the framework for clinical trials designed to enhance sensitivity and overcome resistance to bortezomib [Velcade], thereby improving patient outcome in multiple myeloma."

Possible link between leukaemia and overhead power lines

Fri, 03 Jun 2005 16:47:00 PST

( from http://www.rxpgnews.com ) Children living close to high voltage overhead power lines at birth may be at an increased risk of leukaemia, finds a large study in this week's BMJ.

But the authors emphasise that these results may be due to chance and further research is needed to find out whether there really is a link.

The authors will present their full findings at an embargoed press briefing on Thursday 2 June 2005 at 11.00am, BMA House, London, UK.

About one child in 2000 develops leukaemia before the age of 15 years.

Although we don't yet understand its causes, researchers have studied a variety of possible explanations including genetic susceptibility, ionising radiation, unusual patterns of exposure to infection, and electromagnetic fields.

The electric power system produces extremely low frequency electric and magnetic fields, and since 1979 there has been concern that these fields may be associated with cancer. In 2001, the International Agency for Research on Cancer classified extremely low frequency magnetic fields as "possibly carcinogenic" while others, such as the UK Childhood Cancer Study, dispute the risk.

Over 29,000 children with cancer, including 9,700 with leukaemia, were included in the study, the largest of its kind to date. The children were aged 0-14 years and were born in England and Wales between 1962 and 1995. They were compared with a group of control children individually matched for sex, approximate date of birth, and birth registration district. The distance of each child's home address at birth from the nearest high voltage power line was calculated.

Children who lived within 200m of high voltage power lines at birth appeared to have a 70% raised risk of leukaemia compared with those who lived beyond 600m. There was also a slightly increased risk for those living 200-600m from the lines at birth.

To put these risks into perspective, about five of the 400-420 cases of childhood leukaemia that occur annually in England and Wales may be associated with power lines.

No excess risk was found for other childhood cancers.

The finding that the increased leukaemia risk extends so far from the line is surprising in view of the low average level of exposure to magnetic fields at these distances, say the authors. There is no accepted biological mechanism to explain these results; indeed, the relation may be due to chance or some other factor associated with living near power lines.

In an accompanying editorial, Heather Dickinson from the University of Newcastle upon Tyne agrees that, even if the effect is causal, it could account for only a tiny proportion of cases.

She says, "Magnetic fields from power lines are very weak only about 1% of the earth's magnetic field which affects all of us all the time so it would be surprising if they caused leukaemia. The increased risk closer to power lines may reflect some other factor that varies geographically." The study didn't measure the magnetic field from either the power lines or other sources.

"We don't yet fully understand the aetiology of childhood leukaemia," she says. "Nevertheless, we are now reasonably sure that it often involves damage to DNA before birth, and an unusual pattern of exposure to infections after birth.

Further insights into the causes of childhood leukaemia will almost certainly come through advancing technology helping us understand the molecular events which drive leukaemic changes," she concludes.

Removing the spleen may help fight leukemia

Thu, 02 Jun 2005 16:05:00 PST

( from http://www.rxpgnews.com ) Early surgical removal of the spleen combined with antiangiogenic cancer therapy may halt the progression of leukemia, according to scientists at Sunnybrook and Women's College Health Sciences Centre.

The research, published today in Blood, is the first to show the combination of two factors secreted from the environment of the spleen is important in the promotion of leukemia.

Dr. Yaacov Ben-David, a Senior Scientist in Molecular and Cellular Biology at the Sunnybrook & Women's Research Institute who is the lead investigator in the study and colleagues, including Dr. Yuval Shaked, a post-doctoral fellow, discovered that the spleen of diseased mice provides a supportive environment for cancer cells. The spleen secretes various factors, among them MCP and VEGF, which relate to the immune system and promote formation of new blood vessels. Secretions of these factors cause leukemic cells in the spleen to multiply. In this study, Dr. Ben-David's team showed that these factors might contribute to the progression of breast and other types of cancer.

"For the first time we have been able to provide evidence that the environment around the spleen may play a critical role for patients with leukemia and possibly other types of cancers," says Dr. Ben-David who is also an Associate Professor of Medical Biophysics at the University of Toronto. "When combined with antiangiogenic cancer therapies that work by halting the development of new blood vessels that feed tumor growth, we found that mice experienced prolonged survival."

In the human body, the spleen is located in the upper left side of the abdomen, behind the stomach. Its functions are to filter blood, remove bacteria and make and store blood. Since it is involved in so many bodily functions, it is vulnerable to a wide range of disorders. Any condition that infects the spleen, such as leukemia, can place great strain on the organ and cause it to enlarge. The human body can adapt well to life without this organ, so surgically removing a diseased or damaged spleen is worth further investigation.

Researchers suggest that early surgical intervention by removing the spleen and suppressing the related factors might be considered as a treatment model for human hematological malignancies, cancers of the body's blood-forming and immune systems. Since the research was conducted on mice and does not apply to humans, further research and clinical trials are required before this is practice will be considered as a treatment option in the clinic.

FDA Gives Clearance to GRN163L for Treatment of Chronic Lymphocytic Leukemia

Mon, 23 May 2005 20:20:00 PST

( from http://www.rxpgnews.com ) Geron Corporation (Nasdaq:GERN) announced today that it has obtained clearance from the U.S. Food and Drug Administration (FDA) to initiate clinical testing of its lead anti-cancer compound, GRN163L, in patients with chronic lymphocytic leukemia (CLL). The company filed its first Investigational New Drug Application (IND) for GRN163L in April 2005.

"Acceptance by the FDA of our first IND submission for GRN163L is an important milestone," said Melissa Kelly, Geron's vice president of oncology. "We have three clinical trial sites selected and expect to begin treating patients next month."

The initial Phase I/II, open-label, dose-escalation trial of GRN163L will be conducted in patients with advanced CLL. The study is designed to demonstrate the safety and tolerability of GRN163L administered on a weekly intravenous dosing schedule.

Pharmacokinetic and pharmacodynamic parameters will also be studied. Importantly, CLL provides a unique opportunity to measure both the magnitude and time course of telomerase inhibition in tumor cells. By serially assessing the effects on the target enzyme in CLL cells, we will attempt to define both a dose and a dosing interval that effectively inhibits telomerase activity. This will provide useful data for designing further clinical studies of GRN163L, including combination studies with other approved cancer therapies.

About GRN163L

GRN163L is a potent inhibitor of telomerase. Inhibition of telomerase activity by GRN163L in cancer cells results in telomere shortening, and leads to cell cycle arrest or apoptosis.

GRN163L is a 13-mer oligonucleotide N3' -- P5' thio-phosphoramidate (NPS oligonucleotide) that is covalently attached to a C16 (palmitoyl) lipid moiety. GRN163L binds directly with high affinity to the template region of the RNA component of human telomerase (hTR), which lies in the active or catalytic site of hTERT, the telomerase reverse transcriptase. GRN163L binding to hTR results in direct, competitive inhibition of telomerase enzymatic activity.

GRN163L has been characterized preclinically and shown to inhibit telomerase in human tumor cells of many cancer types, in both cell culture systems and animal models. Studies of this agent alone, and in combination with chemotherapeutic agents, indicate the importance of telomerase as a target for the treatment of cancer, and the potential utility of GRN163L in the treatment of patients with hematologic and solid tumor malignancies.

About Chronic Lymphocytic Leukemia (CLL)

CLL is the most common form of leukemia in adults in the Western world. According to the American Cancer Society, an estimated 9,700 patients in the United States will be diagnosed with CLL in 2005. CLL results from an acquired mutation in a single cell in the bone marrow. This change in the cell's DNA causes it to become malignant, and results in the uncontrolled growth of abnormal lymphocytes in the bone marrow leading to an increase in the number of abnormal lymphocytes in the blood. Lymphocytes are a type of white blood cell that normally produce antibodies and play an important role in fighting infections. Patients with CLL typically develop symptoms that may progress over a number of years and include a decrease in immunity, marked increase in the size of lymph nodes, spleen, and liver, and impaired production of other normal blood cells. Eventually, these changes may cause life-threatening complications, such as profound infections and fatal bleeding.

Lenalidomide Can Replace Blood Transfusions in Bone Marrow Disorder

Wed, 18 May 2005 01:45:00 PST

( from http://www.rxpgnews.com ) A new study reports that the drug lenalidomide (RevLimid) can help some patients with myelodysplastic syndromes (MDS) avoid the need for blood transfusions, and even reduce or eliminate the genetic abnormality that characterizes the disease in this subset of patients.

Lenalidomide is an anti-angiogenic agent that is similar to thalidomide.

Myelodysplastic syndromes are a group of cancers in which the bone marrow does not make enough mature, functional blood cells. Patients commonly undergo blood transfusions every eight weeks to manage symptoms of anemia and fatigue caused by low red blood cell counts. MDS is the most common cancer of the blood in adults more common than leukemia affecting 40,000 to 50,000 Americans every year.

"Lenalidomide is a breakthrough for patients with MDS. This is the first effective therapy for this specific subtype of disease," said lead author Alan F. List, MD, Professor of Medicine at the H. Lee Moffitt Cancer Center in Tampa, Florida. Lenalidomide, which is taken orally, may work against MDS by inhibiting angiogenesis (the growth of blood vessels that tumor cancers need to grow), boosting the body's immune response against cancer, and enhancing red blood cell development.

Investigators examined the response to 10 mg of once-daily lenalidomide among 146 patients with MDS who relied on blood transfusions. All patients had a deletion of a region of genetic material on the long "q" arm of chromosome 5 ("del5q"). The trial was initiated in July 2003, and monitoring is ongoing. All patients who responded to the drug are continuing to take it as long as it remains effective.

After 24 weeks, 64% of patients responded to lenalidomide and did not need a transfusion. Seventy-six percent of those who responded experienced a reduction in the number of marrow cells that had the del5q abnormality, and 55% of responders had no evidence of the del5q abnormality. After a median follow-up of 9.3 months, 91% of responding patients continued to show a response to lenalidomide. The most common side effects were lowering of the white blood cell count (39% of patients) and platelet count (35%), which necessitated interruption of treatment or reduction of lenalidomide dose.

Oblimersen Shows Promising Results in Older Patients with Acute Myeloid Leukemia

Fri, 06 May 2005 10:20:00 PST

( from http://www.rxpgnews.com ) Researchers from Ohio University, University of Chicago, the National Cancer Institute and Genta, Inc. have reported a promising phase I study of Genasense (oblimersen) in untreated older patients with acute myeloid leukemia (AML). The details of this study appeared as an advanced on-line publication in the Journal of Clinical Oncology on April 11, 2005.[1]

Bcl-2 is a potent inhibitor of apoptosis which is a cause of cell death. Over-expression of this protein in patients with leukemia is associated with resistance to chemotherapy.

The Bcl-2 antisense oligonucleotide, Genasense down-regulates Bcl-2 and has been investigated in several hematological malignances where Bcl-2 has been implicated in disease resistance. In vitro studies have suggested that Genasense can down-regulate Bcl-2 activity and inhibit cell viability. Thus, the targeting of Bcl-2 was a potential strategy for treatment of leukemia. These same researchers previously reported the results of treatment of patients with refractory AML with the combination of Fludara®, cytarabine, Genasense and Neupogen®.[2]

Seventeen patients in this study had relapsed or refractory AML and 3 had acute ALL, including 2 patients who had failed stem cell transplantation. Five patients with AML and one patient with ALL achieved a complete response. Three other patients had disappearance of blasts but did not achieve full hematological recovery. In two patients, the response persisted for over one year before recurrence. Responses were also seen in older patients. The researchers also reported that Bcl-2 mRNA levels were down-regulated in 75% of evaluable patients.

The current study included 29 patients who were 60 years of age or older with newly diagnosed AML. All received treatment with cytarabine, daunomycin and Genasense. Complete remissions occurred in 14 patients (48%). Seven of these 14 patients have relapsed. They suggested that the degree of down regulation of Bcl-2 correlated with response. These authors stated that CALGB would be performing a randomized trial in older patients with newly diagnosed AML to determine the contribution of Genasense.

Comments: Its impossible to tell from this study whether or not Genasense contributed to outcome and the randomized trial will be of great interest.

FDA to Discuss the Efficacy of Tipifarnib in Acute Myeloid Leukemia

Thu, 05 May 2005 06:53:00 PST

( from http://www.rxpgnews.com ) The efficacy rate of Johnson & Johnson's oncologic Zarnestra (tipifarnib) in acute myeloid leukemia is likely to be the focus of discussion in FDA's Oncologic Drugs Advisory Committee's review on May 5.

FDA found a confirmed 11% complete response rate with Zarnestra, while J&J reported a 15% rate of complete responses.

J&J is seeking an indication for Zarnestra for 'treatment of elderly patients with newly diagnosed poor-risk acute myeloid leukemia.'

Zarnestra efficacy was primarily established in the 135-patient Cancer Therapy Evaluation Program-20 (CTEP-20) trial in patients with poor-risk AML. The trial enrolled poor-risk AML patients 65-74 years old with previously diagnosed myelodysplastic syndromes or over 75 years of age.

FDA found an 11% CR rate for the trial based on "the sponsor-appointed independent reviewer's assessment of CR's, i.e., 15 subjects with confirmed complete responses," FDA's briefing document states.

J&J, meanwhile, said it identified 20 subjects (15%) as exhibiting complete responses.

The discrepancy lies in J&J's inclusion of two patients, for whom bone marrow slides were unavailable and three patients without CRs confirmed by repeat bone marrow aspirate.

Of the two patients lacking bone marrow slides, one was a confirmed complete responder and one was unconfirmed, J&J's briefing document states.

J&J maintains that the three patients without bone marrow aspirates had peripheral blood counts that confirmed a complete response.

The only other AML therapy indicated specifically for the elderly population, Wyeth's Mylotarg (gemtuzumab ozogamicin), was associated with a 16% complete remission rate in a Phase II trial.

During ODAC's 2000 review of Mylotarg, committee members considered the response rate marginal. However, the panel recommended accelerated approval due to the oncologic's favorable adverse event profile relative to available AML therapies.

Zarnestra would be indicated for a different population than Mylotarg, which is approved as a second-line therapy for elderly CD33+ AML patients who are not candidates for cytotoxic agents.

J&J finished submission of the oncologic under the agency�s Continuing Marketing Application Pilot I program in December, setting a user fee deadline of June 29.

FDA awarded Zarnestra fast-track status due to the potential for the oncologic to meet an unmet medical need.

Currently available AML treatments are associated with treatment-induced mortality rates of as high as 25% in poor-risk patients, FDA noted.

Zarnestra's adverse event profile may make it more attractive for use in the poor-risk AML population.

In CTEP-20, one patient died of Zarnestra-related adverse events (neutropenia, fungal infection and renal dysfunction).

Grade 3 or 4 treatment-emergent adverse events occurred in 83% of patients, and 61% experienced drug-related events. Serious adverse events appearing in greater than 10% of patients were neutropenic fever (41%), infections (27%), thrombocytopenia (17%), fatigue (13%) and pneumonia (10%).

Another advantage for Zarnestra could be its oral dosing (600 mg twice daily), allowing patients to receive treatment outside of a hospital setting. Mylotarg is administered by infusion.

J&J has initiated enrollment for a Phase III confirmatory study of Zarnestra in AML. The study will compare tipifarnib to best supportive care in newly diagnosed AML patients 70 years and older. The sponsor expects study results by the end of 2006.

Wyeth has yet to complete its confirmatory study for Mylotarg due to patient accrual problems. The company expects to complete patient accrual by 2007 and to submit the study to FDA by 2010, a decade after gemtuzumab�s accelerated approval.

Tipifarnib failed to show efficacy previously in trials in pancreatic and colorectal cancer.

Day Care in Infancy Protects Against Childhood Leukaemia

Fri, 29 Apr 2005 14:29:00 PST

( from http://www.rxpgnews.com ) Children who attend day care centres on a regular basis in the first few months of life are less likely to develop leukaemia than children who do not, finds a study published online by the BMJ today.

These results support the theory that reduced exposure to common infections in the first year of life increases the risk of developing acute lymphoblastic leukaemia (ALL).

The study involved 6305 children (aged 2-14 years) without cancer, 3140 children with cancer (diagnosed 1991-6), of whom 1286 had ALL. Parents were interviewed about day care and social activity with children outside the family during the first year of life.

Increasing levels of social activity outside the home were associated with consistent reductions in risk of ALL. However, the greatest reduction in risk of ALL was seen in children who attended formal day care during the first three months of life (defined as attendance at a day nursery or nursery school at least once a week, or at least two half day sessions a week at a playgroup, mother and toddler group, or at a childminder with a minimum of four children attending).

Results were similar for cases diagnosed between 2-14 years and for cases diagnosed between 2-5 years.

"Our results provide further support that social activity with other infants and children during the first few months of life protects against subsequent risk of ALL," say the authors.

The most plausible interpretation is that this protection comes from exposure to common infections. Similar associations have been reported for type 1 diabetes and allergies in children.

"Whether early exposure to one or more specific infections, or to a spectrum of non-specific agents, protects against each of these disparate diseases remains to be clarified. Nevertheless, we conclude that some degree of early exposure to infection seems to be important for child health."

Pathways leading to childhood leukaemia identified

Mon, 25 Apr 2005 19:32:00 PST

( from http://www.rxpgnews.com ) The leading UK leukaemia research charity (LRF) reveals today (Friday) that major sign-posts along the pathways leading to childhood leukaemia have been identified.

The findings come from the largest and most comprehensive investigation of childhood leukaemia and other cancers ever undertaken anywhere in the world The United Kingdom Childhood Cancer Study (UKCCS)1.

At a meeting earlier this week to examine the results of this 15-year study, world experts discussed the possible causes of childhood leukaemia. They confirmed that most childhood leukaemias have their origins before birth, but that later infectious events in infancy and childhood may trigger an abnormal immune response leading to disease. They further agreed that the timing of exposure to common infections in infancy and later in childhood was critically important.

This unique project interviewed parents, and collated biological material and clinical records of 3,838 children diagnosed with cancer, including 1737 with leukaemia. A comparison group of further 7,629 children without cancer was also studied.

As well as looking at immunological pathways, other exposures evaluated included household levels of background radiation (ionising and electromagnetic), parental smoking and occupation, breast-feeding and neonatal vitamin K administration, as well as a wide range of factors occurring during pregnancy and shortly after birth.

Chairman of the LRF Medical & Scientific Advisory Panel Sir Walter Bodmer FRS comments: "Understanding causation and thereby finding ways to prevent childhood leukaemia is a key objective for the Leukaemia Research Fund. Our investment of several million pounds in the 15-year UKCCS project has been rewarded with a much clearer idea of why, when and how children get leukaemia.

"The most plausible explanation now seems to be a challenge to the child's immune system, quite possibly involving common infections, which cause the cancerous blood cells to emerge. How such a challenge triggers leukaemia remains a puzzle to be solved, as is the role of inherited susceptibility."

Professor Mel Greaves FRS, Head of the Section of Haemato-Oncology, The Institute of Cancer Research, comments: "The UKCCS project has been the most exhaustive and detailed study ever conducted into identifying possible causes of leukaemia in children.

"Analysis of the huge amount of data collected from over 1,500 families who had a child diagnosed with leukaemia during the course of the study is still ongoing.

"However, it is clear that perceived risk factors such as living near sources of electromagnetic fields or natural radiation like radon are not principal causes, if at all, of leukaemia in children.

"The epidemiological evidence fits with the known biology of the disease and points to an abnormal response in a child's immune system to infection favouring the outgrowth of blood cells which have been carrying a chromosomal/genetic lesion acquired before birth during foetal development. The timing or pattern of infections very early in life appears to be critical as is, most probably, the genetic background of the individual at risk."

New data presented at the conference confirmed that the majority of childhood leukaemias probably arise as a consequence of an abnormal immunological response to one or more common infections. Furthermore, children with a wide range of social contacts outside the home during infancy appear to have lower rates of leukaemia.

Exposure to infections in the first months and years of life is known to be necessary for normal immune system development, and scientists believe that children who are not exposed may be more likely than those who are to develop leukaemia and perhaps other common diseases of childhood in affluent societies.

A study similar to the UKCCS model is currently underway in California. Professor Pat Buffler, School of Public Health, University of California Berkeley comments: "The Northern California Childhood Leukemia Study has investigated delayed social contact in day care and the risk of childhood leukaemia using comparable methods to UKCCS.

"The study has shown a highly significant relationship of a lower leukaemia risk with higher child hours of exposure to infectious agents as estimated from day care attendance. There is still much to learn about the mechanisms underlying this immune response and the association with leukaemia risk as well as the role of other environmental exposures and genetic susceptibility.

"For the first time in the long history of research into the causes of childhood leukaemia we now have the biological and epidemiological foundations to begin a consideration of preventive measures."

Bortezomib Based Therapies may Become the New Standard of Care in Multiple Myeloma

Thu, 14 Apr 2005 20:57:00 PST

( from http://www.rxpgnews.com ) Millennium Pharmaceuticals, Inc. (Nasdaq: MLNM - News) today announced the presentation of positive clinical results for VELCADE in treating patients across the multiple myeloma (MM) treatment paradigm at the 10th Annual International Myeloma Workshop (IMW) in Sydney, Australia. Data regarding the use of VELCADE as a single agent and in combination with standard and emerging MM therapies were reported at the meeting.

Data presented provided evidence for the potential of VELCADE to induce higher response rates in earlier lines of therapy. Front- line studies of VELCADE were the highlight of several scientific sessions and showed very high response rates in previously untreated MM patients with manageable toxicities.

These studies were the basis for three large, multicenter, independent phase III studies. VELCADE is approved in the U.S. for the treatment of patients who have received at least one prior therapy.

"These front-line data suggest VELCADE may offer a new option for patients with multiple myeloma who have not yet been treated," said David Schenkein, M.D., senior vice president, clinical research, Millennium. "While VELCADE is the only single agent to demonstrate a statistical survival advantage in relapsed patients, the benefits in combination with other therapies confirm our belief that VELCADE based therapies can become the new standard of care in multiple myeloma."

The following is summary data from clinical studies of VELCADE presented at the IMW:

Front-line treatment in MM patients

In five investigator-initiated studies of VELCADE, two conducted by cancer cooperative groups, outcomes reported in combination with standard and emerging therapies included overall response rates of up to 95 percent and high complete and near complete response rates of up to 32 percent. A complete and near complete response rate of 57 percent was reported following single stem cell transplant preceded by induction with VELCADE/adriamycin/ dexamethasone (PAD). This response rate was similar to the complete response rate reported for tandem transplants. Front-line data showed patients were able to have successful stem cell harvest and transplantation after VELCADE® (bortezomib) for Injection.

In the front-line phase II Cancer and Leukemia Group B (CALGB) study, an initial report of responses in combination with liposomal doxorubicin showed complete and partial responses in 12 of 15 patients and no patients have progressed so far on study. Toxicities in this study were similar to the phase I study in which high response rates in relapsed or refractory patients prompted this front-line investigation. Other front-line combinations presented were VELCADE with high-dose dexamethasone and VELCADE with melphalan/prednisone. In these five studies overall, adverse events were found to be manageable and included gastrointestinal, asthenic conditions, hematologic, neurologic, skin toxicity, musculoskeletal and pyrexia. Positive results from these front-line studies have led to three large, international, randomized, phase III trials; two of which are being conducted by cooperative groups.

Second-line MM

In a phase III, multicenter trial comparing single agent VELCADE to high-dose dexamethasone, VELCADE demonstrated a 45 percent response rate, including an approximate 13 percent complete (6.25 percent) and near complete response rate (6.25 percent). Importantly, a longer duration of response and a statistically significant survival advantage were found in patients who had received only one prior therapy. Results showed that the probability of death with dexamethasone was 2.56 times that of VELCADE therapy. Side effects were as expected from prior experience with VELCADE, were manageable and peripheral neuropathy improved or reversed in nearly half of all patients. The most common adverse events reported in this study as related to VELCADE were gastrointestinal, neurologic, musculoskeletal and hematologic. These data were the basis of the recent FDA approval for VELCADE use in MM patients who have received at least one prior therapy.

Relapsed or refractory MM

Investigator-initiated studies demonstrated VELCADE was well tolerated and provided a high overall response rate as both a single agent and in combination with standard and emerging therapies, such as liposomal doxorubicin/thalidomide, melphalan and lenalidomide. In combination studies, the response rates of more than 60 percent in heavily pre-treated patients without additive toxicities showed the compatibility of VELCADE with these agents. Other combinations presented were VELCADE plus dexamethasone and VELCADE plus intravenous melphalan.

About Multiple Myeloma

MM is the second most common blood cancer and although the disease is predominantly a cancer of the elderly (the average age of onset is 65 to 70 years of age), recent statistics indicate both increasing incidence and younger age of onset. In the United States, more than 40,000 individuals have MM and over 14,000 new cases of the disease are diagnosed each year. Worldwide there are approximately 74,000 new cases and over 45,000 deaths due to multiple myeloma each year.

About VELCADE® (bortezomib) for Injection

VELCADE is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

Risks associated with VELCADE therapy include new or worsening peripheral neuropathy, hypotension, cardiac disorders, gastrointestinal adverse events, thrombocytopenia and tumor lysis syndrome. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE.

In 331 patients who were treated with VELCADE 1.3 mg/m2 dose in the phase III APEX study, the most commonly reported adverse events were asthenic conditions (61%), diarrhea (57%), nausea (57%), constipation (42%), peripheral neuropathy (36%), vomiting (35%), pyrexia (35%), thrombocytopenia (35%), psychiatric disorders (35%) and anorexia and appetite decreased (34%). Fourteen percent of patients reported at least one episode of grade 4 toxicity; the most common grade 4 toxicities were thrombocytopenia (4%), neutropenia (2%) and hypercalcemia (2%). A total of 144 patients on VELCADE (44%) reported serious adverse events (SAEs) during the study. The most commonly reported SAEs were pyrexia (6%), diarrhea (5%), dyspnea and pneumonia (4%) and vomiting (3%).

VELCADE is being co-developed by Millennium and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Millennium is responsible for commercialization of VELCADE in the U.S.; Ortho Biotech and Janssen-Cilag are responsible for commercialization in Europe and the rest of the world. Janssen Pharmaceutical K.K. is responsible for Japan. VELCADE is approved in more than 40 countries worldwide including the U.S., European Union members, and a number of countries within Latin America and South-East Asia such as Argentina, China, Korea, Singapore and Thailand.

Lenalidomide: A Novel Class of Immunomodulatory Drugs for Treatment of Myelodysplastic Syndromes

Sat, 09 Apr 2005 10:31:00 PST

( from http://www.rxpgnews.com ) Celgene Corporation (Nasdaq: CELG - News) announced that it has completed the rolling submission of its New Drug Application (NDA) for REVLIMID (lenalidomide), an investigational drug, to the Division of Oncology Drug Products at the U.S. Food and Drug Administration (FDA) for review. The Company's NDA is seeking approval to market REVLIMID as a treatment for transfusion-dependent patients with myelodysplastic syndromes (MDS) with a 5q deletion chromosomal abnormality.

MDS is a malignant disorder of blood cell production that affects approximately 300,000 people worldwide. The most common clinical manifestation associated with MDS is refractory anemia, and the multiple complications that stem from frequent blood transfusions.

Celgene's lead IMiD® (Immunomodulatory drug), REVLIMID has received both orphan drug status and fast track designation from the U.S. Food and Drug Administration (FDA) and orphan drug status from the European Agency for the Evaluation of Medicinal Products for the treatment of MDS.

"Celgene appreciates and acknowledges the efforts of all those who made this filing possible, including: the more than 400 patients who participated in these MDS studies, and the international community of clinical investigators who have helped us get to this stage in the regulatory process." said Jerome B. Zeldis, M.D., Ph.D., Chief Medical Officer and VP, Medical Affairs of Celgene Corporation.

About REVLIMID®

REVLIMID is a member of a new class of novel immunomodulatory drugs, or IMiDs®. Celgene is evaluating treatments with REVLIMID for a broad range of hematology and oncology conditions, including; multiple myeloma, the malignant blood cell disorders known as myelodysplastic syndromes (MDS) as well as solid tumor cancers.

REVLIMID affects multiple intracellular biological pathways. The IMiD pipeline, including REVLIMID, is covered by a comprehensive intellectual property estate of U.S. and foreign issued and pending patent applications including composition-of-matter and use patents.

REVLIMID® (lenalidomide) is not approved by the FDA or any other regulatory agencies as a treatment in any indication and is currently being evaluated in clinical trials for efficacy and safety for future regulatory applications.

About Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are a group of hematologic malignancies that affect approximately 300,000 people worldwide. Myelodysplastic syndromes occur when blood cells remain in an immature or "blast" stage within the bone marrow and never develop into mature cells capable of performing their necessary functions. Eventually, the bone marrow may be filled with blast cells suppressing normal cell development.

According to the American Cancer Society, 10,000 to 20,000 new cases of MDS are diagnosed each year in the United States, with mean survival rates ranging from approximately six months to six years for the different classifications of MDS. MDS patients must often rely on blood transfusions to manage symptoms of anemia and fatigue until they develop life-threatening iron overload and/or toxicity, thus underscoring the critical need for new therapies targeting the cause of the condition rather than simply managing its symptoms.

About 5q Deletion Chromosomal Abnormality

Chromosomal (cytogenetic) abnormalities are detected in more than half of patients with myelodysplastic syndrome (MDS), and involve a deletion in all or part of one or more specific chromosomes. The most common cytogenetic abnormalities in MDS are deletions in the long arm of chromosomes 5, 7, and 20. Another common abnormality is an extra copy of chromosome 8. A deletion involving the 5q chromosome may be involved in 20 to 30% of all MDS patients.

The World Health Organization has also recently identified a unique subset of MDS patients with a "5q- Syndrome" where the only chromosomal abnormality is a specific portion of the 5q chromosome.

Tipifarnib to be Reviewed for its Indication in Acute Myeloid Leukemia

Wed, 06 Apr 2005 07:03:00 PST

( from http://www.rxpgnews.com ) The Oncologic Drugs Advisory Committee will review Johnson & Johnsons Zarnestra (tipifarnib) May 5.

J&J is seeking an indication for treatment of patients 65 years and older with newly diagnosed acute myeloid leukemia.

The firm completed submission for the farnesyl transferase inhibitor Dec. 29 under the Continuous Marketing Application Pilot 1 program, setting a six-month review clock.

The NDA is based on Phase II studies using non-survival endpoints. A Phase III trial to fully demonstrate the clinical benefit of tipifarnib was initiated in October 2004.

J&Js Tibotec subsidiary is handling Zarnestras development. Other areas of potential utility include RAS-dependent tumors, for which Phase III studies are underway.

J&J is focusing on RAS-dependent tumors that are not colorectal or pancreatic, since earlier trials showed no benefit over standard of care in either cancer.

Zarnestra is also in development for treatment of a range of myeloid leukemia stages.

Genetically Modified Natural killer ( NK ) Cells can be Used to Kill Leukemic Cells

Tue, 29 Mar 2005 09:25:00 PST

( from http://www.rxpgnews.com ) Natural killer ( NK ) immune system cells can be genetically modified to brandish a powerful "on-switch" that prompts them to aggressively attack and kill leukemic cells. This finding, from researchers at St. Jude Children's Research Hospital, suggests a way to improve the outcome of children who receive treatment for acute lymphoblastic leukemia ( ALL ) or other blood cancers.

Results of the St. Jude study are published in the current online issue of Blood.

The researchers demonstrated how to overcome significant technical hurdles that have until now slowed development of NK-based therapies for ALL, according to Dario Campana, M.D., Ph.D., a member of St. Jude Hematology-Oncology and Pathology, and senior author of the Blood report.

Progress in adapting NK cells to the treatment of ALL had been significantly hampered because researchers were not able to grow large numbers of these immune cells in the laboratory, and because NK cells normally have only weak anti-leukemic activity.

The key breakthroughs made by the St. Jude team were the development of a laboratory technique for rapidly producing a large, pure population of NK cells from a small sample of blood; and developing a technique for genetically modifying NK cells so that they would become potent killers when they encountered leukemic cells.

In order to grow large populations of NK cells, the team started with samples of blood containing a variety of different immune system cells. They placed this sample into a dish containing a type of human leukemia cell called K562. Campana's team genetically modified the K562 cells so they carried on their surfaces many copies of two different proteins, 4-1BBL and IL-15.

The genetically modified K562 cells quickly stimulated the expansion of the NK cell population to more than10,000 times their original number. The technique triggered growth of NK cells specifically, which greatly simplified the ability of the researchers to collect a pure population of these immune cells.

The researchers then genetically modified the growing NK cells so they carried on their surface an artificial receptor that made them particularly aggressive and effective killers that attacked only leukemic cells.

A receptor is a protein that binds to a specific target molecule. The artificial receptor on the NK molecule was designed to recognize a protein called CD19, which is found on the surface of leukemic cells. When the receptor bound to CD19 on leukemic cells, it set off a reaction that super-charged the killing activity of the NK cell.

"By developing a technique for cultivating large numbers of NK cells from a small blood sample, we made it practical to consider them a potential treatment against many different types of cancer," Campana said. "By genetically modifying NK cells so they expressed the CD19 receptor, we made them specifically effective against ALL cells."

A potential clinical application for the technology developed in this study is in leukemia patients who are treated with hematopoietic ( blood cell-forming ) cell transplantation.

In this case, NK cells will be derived from the transplant donor, expanded and genetically modified. These modified NK cells will then be infused into the patient after the transplant in order to eliminate residual leukemic cells. In another application, NK cells could be obtained from a patient while in remission and then reinfused after genetic modification if the patient suffers a resurgence of the leukemia.

"We look forward to seeing this strategy being added to the management of children with ALL," said Chihaya Imai, M.D., the postdoctoral student who did most of the work on this project.

Genetically Enhanced NK cells developed to Eradicate Leukemia Cells

Sun, 27 Mar 2005 16:15:00 PST

( from http://www.rxpgnews.com ) Natural killer (NK) immune system cells can be genetically modified to brandish a powerful "on-switch" that prompts them to aggressively attack and kill leukemic cells. This finding, from researchers at St. Jude Children's Research Hospital, suggests a way to improve the outcome of children who receive treatment for acute lymphoblastic leukemia (ALL) or other blood cancers.

Results of the St. Jude study are published in the current online issue of Blood.

The researchers demonstrated how to overcome significant technical hurdles that have until now slowed development of NK-based therapies for ALL, according to Dario Campana, M.D., Ph.D., a member of St. Jude Hematology-Oncology and Pathology, and senior author of the Blood report. Progress in adapting NK cells to the treatment of ALL had been significantly hampered because researchers were not able to grow large numbers of these immune cells in the laboratory, and because NK cells normally have only weak anti-leukemic activity.

The key breakthroughs made by the St. Jude team were the development of a laboratory technique for rapidly producing a large, pure population of NK cells from a small sample of blood; and developing a technique for genetically modifying NK cells so that they would become potent killers when they encountered leukemic cells.

In order to grow large populations of NK cells, the team started with samples of blood containing a variety of different immune system cells. They placed this sample into a dish containing a type of human leukemia cell called K562. Campana's team genetically modified the K562 cells so they carried on their surfaces many copies of two different proteins, 4-1BBL and IL-15. The genetically modified K562 cells quickly stimulated the expansion of the NK cell population to more than10,000 times their original number. The technique triggered growth of NK cells specifically, which greatly simplified the ability of the researchers to collect a pure population of these immune cells.

The researchers then genetically modified the growing NK cells so they carried on their surface an artificial receptor that made them particularly aggressive and effective killers that attacked only leukemic cells. A receptor is a protein that binds to a specific target molecule. The artificial receptor on the NK molecule was designed to recognize a protein called CD19, which is found on the surface of leukemic cells. When the receptor bound to CD19 on leukemic cells, it set off a reaction that super-charged the killing activity of the NK cell.

"By developing a technique for cultivating large numbers of NK cells from a small blood sample, we made it practical to consider them a potential treatment against many different types of cancer," Campana said. "By genetically modifying NK cells so they expressed the CD19 receptor, we made them specifically effective against ALL cells."

A potential clinical application for the technology developed in this study is in leukemia patients who are treated with hematopoietic (blood cell-forming) cell transplantation. In this case, NK cells will be derived from the transplant donor, expanded and genetically modified. These modified NK cells will then be infused into the patient after the transplant in order to eliminate residual leukemic cells. In another application, NK cells could be obtained from a patient while in remission and then reinfused after genetic modification if the patient suffers a resurgence of the leukemia.

"We look forward to seeing this strategy being added to the management of children with ALL," said Chihaya Imai, M.D., the postdoctoral student who did most of the work on this project.

FDA Fully Approves Bortezomib for Treatment of Relapsed and Refractory Multiple Myeloma

Sat, 26 Mar 2005 10:02:00 PST

( from http://www.rxpgnews.com ) Millennium Pharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) approved the Company's supplemental New Drug Application (sNDA) for VELCADE(Bortezomib). This approval expands the label to include the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy.

Bortezomib is the only drug therapy that has demonstrated a significant survival advantage as compared to a standard therapy in relapsed MM. Initial accelerated approval for relapsed and refractory MM was granted in May 2003.

Bortezomib is now fully approved in relapsed MM.The approval was based on data from the randomized phase III APEX study that compared single-agent Bortezomib to a traditional MM therapy, high-dose dexamethasone. The study demonstrated a significant survival advantage with
Bortezomib (p less than 0.05) in patients who had received one to three prior therapies.

Importantly, this pronounced survival advantage was also observed in the second-line MM patients. The safety profile of Bortezomib remained consistent with previous phase II findings. This indication doubles the number of U.S.
patients who could potentially benefit from Bortezomib to approximately 22,000.

"We are thrilled that more patients will have access to Bortezomib earlier in their treatment where Bortezomib has shown a significant improvement over a standard therapy in improving survival and delaying disease progression," said
David Schenkein, M.D., senior vice president, clinical research at Millennium.

"Millennium is committed to making a difference in patients' lives and will continue, in partnership with Johnson & Johnson Pharmaceutical Research and
Development L.L.C., to explore extensively the benefits of Bortezomib across the multiple myeloma treatment paradigm as well as in other hematologic and solid tumors."

The approval of this supplementary filing comes approximately 22 months after the initial FDA approval of VELCADE(R) (bortezomib) for Injection.

Bortezomib, the first of a new class of medicines called proteasome inhibitors,is the first treatment in more than a decade to be approved for patients with multiple myeloma, a cancer of the blood.

The sNDA submission was based primarily upon the results of the phase III APEX study, which compared Bortezomib to high-dose dexamethasone. The APEX trial enrolled 669 patients with relapsed multiple myeloma (patients had received one to three prior therapies) at 93 centers in North America, Europe and Israel.

This study was conducted under the direction of Paul Richardson, M.D.,clinical director, Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute. The APEX trial was halted one year early after an independent data
monitoring committee concluded the findings of a pre-specified interim analysis showed a statistically significant improvement in time-to-disease progression in favor of Bortezomib.

In the overall study population, Bortezomib was superior to high-dose dexamethasone based on time to progression (p less than 0.0001), overall survival (p less than 0.05) and response rate (p less than 0.0001).

Additional findings include the following:

-- Overall, 40 percent fewer patients died in the Bortezomib arm relative to the dexamethasone arm;
-- Overall response rate of 38 percent with Bortezomib, with a median duration of response of 8.0 months compared with a response rate of 18 percent, with a median duration of response of 5.6 months for dexamethasone;
-- Six percent of Bortezomib patients had a complete response and 7 percent had a near complete response as compared to less than one percent each with dexamethasone;
-- After a median of 8.3 months of follow-up, improvement in median time to progression was 78 percent with Bortezomib relative to dexamethasone.

Among the 251 second-line multiple myeloma patients (those who had only one prior therapy), Bortezomib was superior based on time to progression (p=0.0019), response rate (p=0.0035) and overall survival (p less than0.05).
Additional findings include the following:

-- Overall, 55 percent fewer patients died in the Bortezomib arm relative to the dexamethasone arm;
-- Overall response rate with Bortezomib was 45 percent (median duration of response was 8.1 months) compared with 26 percent for dexamethasone (median duration of response 6.2 months); and
-- Six percent of Bortezomib patients had a complete response and 6 percent had a near complete response as compared to two percent each with dexamethasone.

Adverse events on the Bortezomib arm were predominantly grade one or two,were similar to those previously observed in other trials and were considered manageable by the investigators.

-- The most commonly reported adverse events were asthenic conditions,diarrhea, nausea, constipation, peripheral neuropathy, vomiting,pyrexia, thrombocytopenia, psychiatric disorders and anorexia and appetite decreased;
-- The most commonly reported serious adverse events were pyrexia,diarrhea, dyspnea, pneumonia and vomiting.

Bortezomib is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Bortezomib is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

Bortezomib is being co-developed by Millennium and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Millennium is responsible for commercialization of Bortezomib in the U.S.; Ortho Biotech and Janssen-Cilag are
responsible for commercialization in Europe and the rest of the world. Janssen Pharmaceutical K.K. is responsible for Japan.

Risks associated with Bortezomib therapy include new or worsening peripheral neuropathy, hypotension, cardiac disorders, gastrointestinal adverse events,thrombocytopenia and tumor lysis syndrome.

Women of childbearing potential should avoid becoming pregnant while being treated with Bortezomib.

In 331 patients who were treated with Bortezomib 1.3 mg/m2 dose in the phase III APEX study, the most commonly reported adverse events were :

-asthenic conditions (61%),
-diarrhea (57%),
-nausea (57%),
-constipation (42%),
-peripheral neuropathy (36%),
-vomiting (35%),
-pyrexia (35%),
-thrombocytopenia (35%),
-psychiatric disorders (35%) and
-anorexia and appetite decreased (34%)

Fourteen percent of patients reported at least one episode of grade 4 toxicity;the most common grade 4 toxicities were:
-thrombocytopenia(4%),
-neutropenia(2%)
-hypercalcemia(2%).

A total of 144 patients on Bortezomib(44%) reported serious adverse events (SAEs) during the study.The most commonly reported SAEs were pyrexia(6%),diarrhea(5%), dyspnea and pneumonia(4%) and vomiting(3%).

Epstein-Barr virus nuclear antigen protein EBNA3C crucial to its role in blood cancers

Wed, 16 Mar 2005 17:03:00 PST

( from http://www.rxpgnews.com ) Researchers at the University of Pennsylvania School of Medicine have identified a link between a critical cancer pathway and an Epstein-Barr Virus (EBV) protein known to be expressed in a number of EBV-associated cancers. Their findings demonstrate a new mechanism by which EBV transforms human B cells from the immune system into cancerous cells, which can lead to development of B-cell lymphomas.

Using human cell cultures infected with the Epstein-Barr virus, the investigators found that a specific viral protein targets a molecule that normally regulates the cell-cycle progression, or duplication process, of resting B cells. In the presence of this viral protein called EBNA3C (for EBV nuclear antigen) the cell cycle of the usually quiescent human B cells gets a jump start, which ultimately initiates uncontrolled growth.

EBV, a member of the herpesvirus family and one of the most common human viruses, plays a role in cancers such as lymphoproliferative diseases in transplant or AIDS patients, Burkitt's lymphoma, Hodgkin's lymphoma, and nasopharyngeal carcinoma, and also causes the well-known disease, infectious mononucleosis. As many as 95 percent of adults 20 years and older have been infected with EBV, but show no symptoms.

"Viruses that are associated with cancers typically target the cell cycle to gain control," says Robertson. "However, this is the first time that laboratory research into how EBV drives the cancer process has directly identified a critical component of the cell cycle for control. Now we can develop targeted therapeutics to disrupt the function of this viral protein." The researchers surmise that the first use of future therapies from these studies will be in lymphoproliferative disease in transplant and immunocompromised patients because this is a clear case of EBV-driven B-cell lymphoma.

The use of peptides to block the interaction between this essential EBV protein and the specific pathway in human B cells is currently underway. Initial studies show that the growth of EBV-associated cancer cells can be inhibited in tissue-culture assays. The investigators are actively pursuing this line of investigation for developing potential therapies.

VAX100 : A Vaccine for Chronic Myeloid Leukemia (CML)

Wed, 02 Mar 2005 14:34:00 PST

( from http://www.rxpgnews.com ) Breakthrough Therapeutics, a privately owned biotechnology company, today announced the publication of positive data with a vaccine for chronic myeloid leukemia (CML) known as VAX100, in the Journal Lancet.

VAX100 is a BCR-ABL peptide vaccine designed to reduce persistent disease in patients with CML whom have had stable disease during conventional therapy. Breakthrough Therapeutics has licensed the peptides associated with the BCR-ABL breakpoint (including those used in VAX100) from Memorial Sloan Kettering Cancer Center.

Of the six patients whom had previously been treated with interferon alpha for a minimum of 17 months stable residual disease 5 (83%) had improved cytogenetic response with 2 patients achieving CCR. All patients received six injections of VAX100 vaccine on a biweekly schedule. During vaccinations, patients continued conventional treatment. Assessment of cytogenetic response and confirmation of molecular remission took place every 3 months.

Breakthrough is currently optimizing the current formulation of the components of VAX100 to enhance its antigenicity. It will be the optimized formulation, to be named CMLVAX500, which will be taken into additional Phase II trials.

"The best surrogate for long term survival in patients with CML is to achieve a complete molecular remission. While drugs like Gleevec have revolutionized the treatment of CML, not all patients achieve a complete cytogenetic remission and most maintain detectable disease at the molecular level," commented Rosemary Mazanet, M.D., Ph.D., Breakthrough Therapeutics' Co-founder and Chief Executive Officer. "It is our hope that the addition of a BCR-ABL specific vaccine to conventional treatment may further increase the proportion of patients who achieve a reduction of residual disease. The positive results from VAX100 suggest that the enhanced antigenic BCR-ABL peptides may achieve similar results. That would mean a significant step for patients with CML."

David Scheinberg, M.D., Ph.D., Chairman, Molecular Pharmacology & Chemistry, Memorial Sloan-Kettering Cancer Center and the inventor of the BCR-ABL peptide vaccine strategy used by Dr. Monica Bocchia and colleagues commented, "While these data are early we are very encouraged by the results of this study and we look forward to initiating additional clinical trials with our colleagues in the near future."

Sixteen patients with stable residual disease, all of whom received a minimum of either 12 months of imatinib mesylate (Gleevec(R), Novartis) or 24 months of interferon alpha, received a total of 6 vaccinations with VAX100 every other week. Of the 10 patients on imatinib, 9 whom had a median of 10 months of residual disease and 1 patient who started with complete cytogenetic remission (CCR, where cytogenetics are normal on a bone marrow biopsy), all 10 of these patients had improved cytogenetic responses with 50% achieving a CCR. Three of these 5 patients also had undetectable amount of b3a2 transcript (a tumor-specific antigen seen at the fusion point of BCR-ABL).

Chronic myeloid leukemia (CML) is a form of leukemia caused by the abnormal growth of relatively mature white blood (myeloid) cells. CML affects 1 to 2 people in 100,000 and is responsible for 15% to 20% of all adult leukemia. CML is characterized by a specific chromosomal abnormality called the Philadelphia (Ph) chromosome.

The Ph chromosome is the result of a translocation between two genes, which brings together the BCR (breakpoint cluster region) gene on chromosome 22 and the proto-oncogene ABL (Ableson leukemia virus) on chromosome 9. The resulting hybrid gene BCR-ABL activated signaling pathways that lead to uncontrolled cell growth.

Protein promoting stem cell survival might be key to poor leukemia prognosis

Fri, 25 Feb 2005 17:52:00 PST

( from http://www.rxpgnews.com ) The complex and life-sustaining series of steps by which hematopoietic stem cells (HSC) give rise to all of the bodys red and white blood cells and platelets has now been discovered to depend in large part on a single protein called Mcl-1. Mcl-1 blocks the biochemical cascade of reactions that trigger apoptosis (cell suicide) of HSCs, according to Joseph Opferman, Ph.D., assistant member of St. Jude Biochemistry. Expression of Mcl-1 thus ensures that HSCs continue to thrive and multiply so they can complete the task of making huge numbers of blood cells. This process is extremely important during the initial development of the blood system before birth. Expression of Mc1-1 is also crucial for maintaining blood cells throughout life as red and white cells and platelets die and must be replaced. HSCs are also needed to rebuild the blood system of patients undergoing chemotherapy and radiation for cancer. Opferman completed work on this project while a member of Stanley Korsmeyers laboratory at the Dana-Farber Cancer Institute (Boston).

Mcl-1 belongs to the Bcl-2 family of proteins. Some of these family members promote apoptosis, while others prevent it.

Other researchers have previously shown that members of the Bcl-2 family that block apoptosis are involved in regulating the number of HSCs and progenitor cells, Opferman said. But our study showed for the first time that a single such Bcl-2 family proteinMcl-1is essential for promoting the survival of these cells.

Progenitor cells are precursors arising from HSCs; these cells produce daughter cells that become increasingly specialized and then produce specific types of blood cells, such as B lymphocytesimmune cells that produce antibodies.

Understanding the role of Mcl-1 in apoptosis and how this gene is regulated will help my lab at St. Jude understand why some cases of leukemia are so difficult to cure, Opferman said. The more we understand these diseases, the more likely well be able to design improved treatments for them. This fits into the St. Jude mission of finding cures for catastrophic diseases of childhood, such as leukemia, in order to save lives.

The importance of Mcl-1 lies in the differing roles it plays in health and disease.

On one hand, this protein keeps HSCs and progenitor cells alive and multiplying so the body can maintain its needed supply of blood cells, he said. However, Mcl-1 also prevents the abnormal white blood cells found in leukemia from undergoing apoptosis in response to chemotherapy or radiation. This makes the leukemia cells resistant to treatments designed to damage the cell so it undergoes apoptosis.

Opferman is continuing his studies of Mcl-1 at St. Jude to better understand the role this protein plays in both normal hematopoiesis (production of blood cells) as well as in potentially fatal blood cancers.
Opferman and his colleagues had previously shown that Mcl-1 is needed to ensure that HSCs and progenitor cells produced by HSCs are able to generate more specific cells, such as the immune cells known as B and T lymphocytes.

In the Science study, Opfermans team genetically modified mice so that the gene for Mcl-1 could be specifically deleted from the genome of HSCs and progenitor cells. Upon genetic deletion, these mice developed anemia and had severely reduced numbers of bone marrow (BM) cells, such as HSCs and progenitor cells. This was strong evidence that Mcl-1 was needed to maintain these cell populations.

The team also demonstrated that BM cells lacking Mcl-1 did not multiply when removed from mice and cultured in the laboratory. However, BM cells with the gene continued to flourish. In contrast, liver cells were unaffected following loss of Mcl-1, demonstrating that Mcl-1 is important only in certain cell types. Finally, the investigators showed that growth factors (natural proteins that stimulate cells to grow), such as the stem cell factor, trigger the expression of the Mcl-1 gene. This was an important clue to how cells control the powerful effects of Mcl-1.

Recent breakthroughs in common adult leukemia

Thu, 24 Feb 2005 18:31:00 PST

( from http://www.rxpgnews.com ) New England Journal of Medicine (NEJM) recently invited three of the world's foremost experts on chronic lymphocytic leukemia (CLL) to write an authoritative update covering the transformation in the scientific community's knowledge of CLL that has occurred over the past decade. The review appears in the February 24 issue.

Two of the expert authors are with the North Shore-Long Island Jewish (LIJ) Health System (www.northshorelij.com): Nicholas Chiorazzi, MD, director and CEO of the Institute for Medical Research at North Shore-LIJ in Manhasset, NY, who also serves as Professor of Medicine at New York University School of Medicine, and Kanti R. Rai, MB, BS, investigator at the Institute for Medical Research, chief of hematology-oncology at LIJ Medical Center in New Hyde Park, NY, and the Joel Finkelstein Cancer Foundation Professor of Medicine at Albert Einstein College of Medicine. The third author, Manlio Ferrarini, MD, is with the National Institute for Cancer Research in Genoa, Italy (Istituto Nazionale per la Ricerca sul Cancro, Genova, Italia).

"Previous theories about the development and progression of chronic lymphocytic leukemia require revision. With new molecular and protein markers now identified, patients with features that portend poor outcomes may soon be treated earlier and more effectively," said Dr. Chiorazzi.

"Once these new prognostic markers are clinically available to doctors, and after large-scale trials testing early intervention are completed, the 'watchful waiting' practice may be abandoned in many cases," said Dr. Rai, who treats many CLL patients. "New and upcoming discoveries made collectively by us and many other scientists around the world may alter the natural history of this currently incurable leukemia," he added.

A decade ago, CLL was considered a uniform disease of immature white blood cells that didn't die, with the slow rise in leukemia cell count seen in patients due to an accumulation of these immature and incompetent white blood cells. Scientists have since discovered that CLL cells do indeed turn over, with the accumulation over time a result of the difference in the birth and death rates of the leukemia cells.

Scientists have also since discovered that CLL is not a uniform disease but rather a disease that follows two distinct clinical courses in patients. Some patients require no treatment and have a lifespan of more than 20 years after diagnosis. Since the disease most often strikes older adults, the patients whose disease follows this course usually die with the disease, not because of it. CLL may also follow a more aggressive course. In these cases, patients do require chemotherapy and have a lifespan of only about six to eight years after diagnosis despite treatment.

Scientists, including Drs. Chiorazzi, Rai and others at North Shore-LIJ, as well as other research groups in Bethesda, MD, San Diego, CA, and Barcelona, Spain, have identified genetic and protein markers that can predict whether a CLL patient will follow the benign or aggressive course. Some markers are not yet available for clinical use, however according to the review, measurement of one protein marker called ZAP-70 is becoming more widely available. The authors note that ZAP-70 may actually be the most reliable indicator of prognosis known to date.

After discussing B lymphocytes -- the type of white blood cell that gives rise to CLL, the biology of leukemic lymphocytes and the clinical course of CLL as it relates to the biology, the authors then offer a unifying hypothesis for the development, growth and evolution of the disease, and complete the review with a discussion of the clinical implications for practicing physicians.

Feverfew (Bachelor's Button) plant derivative attacks the roots of leukemia

Wed, 23 Feb 2005 19:33:00 PST

( from http://www.rxpgnews.com ) A daisy-like plant known as Feverfew or Bachelor's Button, found in gardens across North America, is the source of an agent that kills human leukemia stem cells like no other single therapy, scientists at the University of Rochester Medical Center's James P. Wilmot Cancer Center have discovered. Their investigation is reported in the online edition of the journal, Blood.

It will take months before a useable, pharmaceutical compound can be made from parthenolide, the main component in Feverfew. However, UR stem cell expert Craig T. Jordan, Ph.D., and Monica L. Guzman, Ph.D., lead author on the Blood paper, say their group is collaborating with University of Kentucky chemists, who have identified a water-soluble molecule that has the same properties as parthenolide.

The National Cancer Institute has accepted this work into its rapid access program, which aims to move experimental drugs from the laboratory to human clinical trials as quickly as possible.

"This research is a very important step in setting the stage for future development of a new therapy for leukemia," says Jordan. "We have proof that we can kill leukemia stem cells with this type of agent, and that is good news."

Parthenolide is the first single agent known to act on myeloid leukemia at the stem-cell level, which is significant because current cancer treatments do not strike deep enough to kill mutant cells where the malignancy is born.

In other words, even the most progressive leukemia treatment, a relatively new drug called Gleevec, is effective only to a degree. It does not reach the stem cells, so "you're pulling the weed without getting to the root," Jordan says.

Feverfew has been used for centuries as an herbal remedy to reduce fevers and inflammation, to prevent migraine headaches, and to ease symptoms from arthritis. (A person with leukemia, however, would not be able to take enough of the herbal remedy to halt the disease.)

Investigating stem cells that give rise to cancer is an urgent new initiative, as is identifying stem-cell treatments that might end the disease process. Jordan and Guzman are among only a handful of stem cell biologists nationwide who are specifically studying cancer stem cells. In recent years, scientists have identified cancer stems cells in blood cancers and in brain and breast tumors although the idea that cancer stems cells exist has been around for at least 40 years.

In the current study, the UR group began investigating Feverfew after other scientists showed that it prevented some skin cancers in animal models. Intrigued by the plant's anti-tumor activities, the UR team analyzed how a concentrated form of parthenolide would act on the most primitive types of acute myelogenous leukemia cells, chronic myelogenous leukemia cells and normal cells.

In laboratory experiments, they also compared how human leukemia stem cells reacted to parthenolide, versus a common chemotherapy drug called cytarabine. The result: parthenolide selectively killed the leukemia cells while sparing the normal cells better than cytarabine.

Scientists believe parthenolide might also make cancer more sensitive to other anti-tumor agents. And, the UR group was able to demonstrate the molecular pathways that allow parthenolide to cause apoptosis, or cancer cell death, increasing the chances of developing a new therapy.

Mouse studies reveal a new methylation target of human leukemia

Mon, 21 Feb 2005 16:28:00 PST

( from http://www.rxpgnews.com ) Researchers in The Ohio State University Comprehensive Cancer Center bred a type of mouse that develops acute lymphoblastic leukemia (ALL). The mouse first goes through a pre-leukemic stage marked by rapidly expanding T cells and natural killer cells, both major components of the immune system. Thanks to a handful of these special mice, scientists have discovered a new tumor suppressor gene and a unique chemical signature implicated in the development of human leukemia, findings that open up a treasure box of opportunity and possibility, study authors say.

In comparing the mice in the pre-leukemic stage and those with ALL with normal mice, researchers found that methylation, a chemical process that adds methyl molecules to DNA, silenced a number of genes but only in the mice with full-blown ALL.

Further tests revealed that the methylation pattern in the mice with leukemia is strikingly similar to the pattern of methylation in human leukemia.

In the process, the researchers also identified a new gene that when methylated, appears to interrupt normal cell death, a process called apoptosis.

It's given us a whole new way to look at and possibly treat leukemia, says Michael Caligiuri, director of the OSU Comprehensive Cancer Center (OSUCCC) and senior co-author of the study. It's also validated our mouse model as a good predictor of what happens in the development of human disease, he added.

We already have a drug, decitabine, that we know can reverse the effects of methylation. We are just beginning to figure out how it best works in humans, but simply knowing that we have a new target that may be meaningful in treating leukemia is a big step in the right direction.

This is the first time anyone has examined methylation in leukemia on a genome-wide basis in a mouse, and the findings offer important implications for patient care, since we know that methylation, which alters gene function, can be reversed, says Christoph Plass, senior co-author and a member of the OSUCCC's Molecular Biology and Cancer Genetics and Experimental Therapeutics Programs.

While it was Caligiuri's laboratory that designed the mouse model, it was Plass who supervised the methylation studies. He and his colleagues used a system called Restriction Landmark Genome Sequencing (RLGS) to compare methylation patterns among the three groups of mice a method of using enzymes and gel electrophoresis to map tiny bits of DNA on a grid. The stretches of DNA, referred to as fragments, show up as smudgy blobs on a test film. If a fragment is dark and definite, it is not methylated. If, on the other hand, it loses at least 30 percent of its intensity, it is regarded as methylated.

In the study, the research team tested 2447 fragments in each animal. They found anywhere from 45 to 209 (.8 percent to 8.5 percent) of the fragments methylated in the mice with cancer, but only one or two methylated fragments in the other mice.

Interestingly, that same range of methylated fragments is exactly what we find in human leukemia, too, says Caligiuri, so that gives added merit to our mouse model as an investigative tool.

Using data from the methylation studies, Caligiuri and Plass were able to identify a particular stretch of DNA, called Id4, as a tumor suppressor gene.

Tumor suppressor genes help control cancer by identifying and getting rid of defective cells before they have a chance to mature and divide. When tumor suppressor genes lose that ability as they can if they are silenced through methylation or some other process, it gives cancer a chance to establish a foothold and spread.

Caligiuri says much more work needs to be done, but adds that the identification of Id4 as a likely tumor suppressor gene gives clinicians another possible target for intervention.

More potent and highly selective therapy with AMN107 effective in treating Gleevec-resistant CML

Sat, 19 Feb 2005 16:53:00 PST

( from http://www.rxpgnews.com ) A laboratory study led by researchers at Dana-Farber Cancer Institute has shown that a potent and highly selective therapy for chronic myelogenous leukemia (CML) may ultimately be more effective than Gleevec®, the current standard of care. The researchers report in the February issue of Cancer Cell that the new compound, AMN107, is about 20 times more potent than Gleevec and is effective in treating Gleevec-resistant disease in model systems. Discovered by and in development with Novartis Pharma AG, AMN107 is a small molecule tyrosine kinase inhibitor.

"While Gleevec represents a major treatment advance for CML approximately 95 percent of patients treated with Gleevec achieve remission there clearly is a need for therapies that produce longer remissions, are active against advanced disease, and can be used when Gleevec loses effectiveness," says Dana-Farber's James Griffin, MD, senior author of the study.

Gleevec shuts down CML by blocking the function of Bcr-Abl, the abnormal tyrosine kinase protein in the leukemic cells that causes them to grow too quickly. However, it does not bind very tightly to this protein, and patients can develop a resistant type of Bcr-Abl that no longer binds to Gleevec at all.

Using rational drug design to circumvent these shortcomings, researchers at Novartis determined the crystal structure of Bcr-Abl, and then constructed compounds that would lock into the receptor more securely than Gleevec. Investigators at Dana-Farber tested the new compounds to measure their effectiveness against CML in laboratory cell cultures and mice with the disease.

Data from the study published in Cancer Cell showed that in experiments with laboratory samples of CML cells, AMN107 killed the cells more effectively than Gleevec. In follow-up studies with mice with a human form of CML, AMN107 produced lengthier remissions than Gleevec and triggered remissions in animals in which the disease had become resistant to Gleevec. Side effects in the animals were minimal.

Synthesized in August 2002, AMN107 entered early Phase I clinical studies in May 2004 21 months later. Data presented last December at the American Society of Hematology showed that AMN107 had demonstrated significant clinical activity in the most challenging setting: Gleevec resistant accelerated and blast crisis CML patients.

"We're very encouraged by the results so far," remarks Griffin, who is also a professor of medicine at Harvard Medical School. "This is an elegant example of how rational drug design developing drugs based on a molecular understanding of cell structures and processes can be used to attack human diseases."

The findings contribute to a larger Dana-Farber research effort, dubbed the "Kinase Project," which seeks to identify abnormal tyrosine kinases -- enzymes that spark or halt growth -- in cancer cells and test agents known to act against them.

Revlimid - new drug breakthorugh in Myelodysplastic Syndrome

Thu, 10 Feb 2005 17:04:00 PST

( from http://www.rxpgnews.com ) Alan List, M.D., leader of the Hematologic Malignancies Program at the H. Lee Moffitt Cancer Center & Research Institute, recently conducted a phase I/II trial of the experimental drug Revlimid showing promise as an innovative way to treat patients with myelodysplastic syndrome (MDS), a form of pre-leukemia. Given in pill form, Revlimid simultaneously blocks the growth of new blood vessels that nourish tumors (anti-angiogenesis) and stimulates the immune system to fight cancer cells. The study is reported in the Feb.10 issue of the New England Journal of Medicine.

Nearly 90 percent of MDS patients are anemic and require regular transfusions of red cells. In this study, 91 percent of the MDS patients with a chromosome abnormality named 5q minus syndrome became transfusion independent. The defective 5q chromosome abnormality may be linked to other serious cancers, including leukemias and small cell lung cancer.

In another finding of the same study, all the patients with the 5q deletion who became transfusion independent also went into cytogenetic remission, meaning that the chromosome abnormality disappeared.

List, a professor of interdisciplinary oncology at the University of South Florida, initially developed the phase I clinical trial of Revlimid for treatment of MDS following his laboratory observations that the agent improved the growth of red blood cell precursors from MDS bone marrow. Celgene will submit the seminal findings of List's phase I trial - along with data from two recent confirmatory phase II clinical trials performed nationwide involving more than 350 patients with red blood cell transfusion-dependent MDS - to the U.S. Food and Drug Administration in a new drug application (NDA) for Revlimid as an innovative approach to treat the anemia of MDS patients with the 5q minus deletion.

In 2001, the National Cancer Institute awarded Moffitt the status of a Comprehensive Cancer Center in recognition of its excellence in research and contributions to clinical trials, prevention and cancer control. Additionally, Moffitt is a member of the National Comprehensive Cancer Network, a prestigious alliance of the country's leading cancer centers, and is listed in the U.S. News & World Report as one of the top cancer hospitals in America. Moffitt's sole mission is to contribute to the prevention and cure of cancer.

Histone Deacetylase (HDAC) Inhibitors For Advanced Multiple Myeloma,reaches Phase II

Wed, 02 Feb 2005 10:58:00 PST

( from http://www.rxpgnews.com ) CuraGen Corporation and TopoTarget A/S today announced the initiation of patient dosing in a Phase II clinical trial evaluating PXD101,a small molecule histone deacetylase (HDAC) inhibitor, as a potential treatment for advanced multiple myeloma, a deadly type of blood cancer.

CuraGen also announced that they have successfully filed an investigational new drug application (IND) for PXD101 to the Food and Drug Administration, allowing initiation of this trial at clinical sites in the United States.

Based on results obtained in Phase I, we are very pleased to advance PXD101 into Phase II and evaluate it as a potential treatment for multiple myeloma," stated William Hahne, M.D., Vice President of Clinical Development at CuraGen. "Throughout 2005, we expect to initiate additional Phase II trials that will investigate PXD101 as a potential treatment for other types of solid and hematologic cancers, and Phase Ib/II studies to explore the safety and activity of PXD101 in combination with other chemotherapy regimens and newer targeted therapies."

This Phase II clinical trial is an open label, multicenter study evaluating the efficacy and safety of PXD101 administered as a single-agent and in combination with dexamethasone, for the treatment of advanced multiple myeloma in patients who have previously failed at least two treatment regimens.

The trial is expected to enroll approximately 50 patients at multiple sites in Europe and the United States. Following enrollment, patients will receive 900 mg/m2/day PXD101 administered intravenously once daily for five consecutive days every three weeks for two cycles. Patients will then be evaluated for tumor response by standard criteria and will either continue receiving up to eight cycles of PXD101 if they demonstrate response or stable disease, or begin combination therapy consisting of PXD101 and dexamethasone. The study is expected to be complete by mid 2006.

Multiple myeloma (MM) is a progressive cancer arising from a particular type of blood cell, called plasma cells. It is the second most prevalent blood cancer in the U.S. with nearly 50,000 individuals suffering from MM, and more than 15,000 new cases expected to be diagnosed this year.

MM is characterized by excessive numbers of abnormal plasma cells in the bone marrow and the overproduction of abnormal immunoglobulins. As a result of MM, patients may develop bone lesions, anemia, elevated blood calcium levels, kidney damage, and a decreased ability to fight off infections. Despite the availability of treatments for MM, there is currently no cure for this disease.

PXD101 is a promising small molecule HDAC inhibitor being investigated for its role in the treatment of a wide range of solid and hematologic malignancies either as a single-agent, or in combination with other active anti-cancer agents, and is currently being evaluated in a Phase II clinical trial for the treatment of multiple myeloma.

HDAC inhibitors represent a new mechanistic class of anti-cancer therapeutics that target HDAC enzymes, and have been shown to: arrest growth of cancer cells (including drug resistant subtypes); induce apoptosis, or programmed cell death; promote differentiation; inhibit angiogenesis; and sensitize cancer cells to overcome drug resistance when used in combination with other anti-cancer agents.

In August 2004, CuraGen signed a Clinical Trials Agreement with the National Cancer Institute (NCI) under which the NCI will sponsor several additional clinical trials to investigate PXD101 for the treatment of various cancers, both as a single-agent and in combination chemotherapy regimens.
~~~~~~~~
TopoTarget is a British/Danish biopharmaceutical company dedicated to the discovery, development and clinical progression of new and improved therapeutics for the cancer patient. The Company was created by the merger of TopoTarget A/S, the Danish oncology company and Prolifix Ltd, the UK based cell cycle company. TopoTarget develops novel pharmaceuticals and aims to identify and market new indications for existing compounds. It applies its precise and in-depth understanding of the molecular mechanisms of cancer with its wide experience in clinical oncology practice to develop new and effective medicines to combat the disease. TopoTarget is based in Copenhagen, Denmark and Oxford, UK. For more information refer to the company's website.

Clinical significance of diminished protein Z in plasma

Sun, 09 Jan 2005 15:18:00 PST

( from http://www.rxpgnews.com ) The clinical significance of diminished protein Z in plasma is controversial. Studies in mice demonstrated that deficiency of protein Z dramatically increases the prothrombotic tendency of factor V Leiden mutation.

This finding was confirmed by initial results in humans, indicating that thromboembolism in factor V Leiden patients with lowered protein Z level occurs earlier than in patients with normal protein Z levels.

Consequently, the aim of our present study was to find out whether genetic alterations of protein Z were demonstrated in patients with factor V Leiden mutation and early onset of thromboembolic disease.

DNA-sequencing of the protein Z gene was performed in two patients with factor V Leiden mutation, early onset of thromboembolism, and lowered protein Z levels. In both patients, R255H substitution of the protein Z gene was identified.

Subsequently, the R255H substitution was also found in 12 of 132 additional patients. Patients presenting with the R255H substitution in addition to factor V Leiden mutation showed thromboembolic events more frequently than factor V Leiden patients without R255H substitution of the protein Z gene.

In conclusion, R255H substitution of the protein Z gene seems to influence clinical symptoms of thromboembolism in factor V Leiden patients.

Model That Predicts Follicular Lymphoma Survival

Fri, 19 Nov 2004 22:03:00 PST

( from http://www.rxpgnews.com ) Scientists at the National Cancer Institute (NCI), part of the National Institutes of Health, have created a model that predicts the survival of follicular lymphoma patients based on the molecular characteristics of their tumors at diagnosis. The model is based on two sets of genes--called survival-associated signatures--whose activity was found to be associated with good or poor prognosis for patients with the cancer. The scientists' results, to be published in the November 18, 2004, New England Journal of Medicine* , suggest that immune cells infiltrating follicular lymphoma tumors have an important impact on survival--both signatures came from such immune cells.

The progression rate of follicular lymphoma, the most common non-Hodgkin lymphoma, varies widely. "In some patients the disease progresses slowly over many years, whereas in others progression is rapid, with the cancer transforming into aggressive lymphoma and leading to early death," explained principle investigator Louis M. Staudt, M.D., Ph.D., of NCI's Center for Cancer Research. "Understanding the molecular causes of such differences in survival could provide a more accurate method to determine patient risk, which could be used to guide treatment and may suggest new therapeutic approaches."

To create their model, Staudt and associates used follicular lymphoma biopsies taken from 191 untreated patients. The biopsies were taken between 1974 and 2001 and came from North American and European institutions that are part of the NCI-sponsored Lymphoma/Leukemia Molecular Profiling Project**. Following their biopsies, all patients received standard treatments. The NCI scientists examined their subsequent medical records to determine survival. Biopsies were divided into two groups balanced for survival and institution: 95 went into a group used to uncover gene expression patterns associated with survival; the other 95 were used to test the predictive power of these patterns.

NCI scientists first used a DNA micro array to determine which genes were expressed (active) in the first group of 95 tumor biopsies, and at what levels. They then determined which of these genes were statistically associated with survival. They called those associated with long survival "good prognosis genes" and those associated with short survival "poor prognosis genes."

Next, the researchers identified subsets of both kinds of genes that tended to be expressed together. These they named "survival-associated signatures." Two signatures--one which indicated poor prognosis, the other good--had strong synergy and together predicted survival better than any other model tested. Unexpectedly, both came from nonmalignant immune cells infiltrating the tumors. The good prognosis signature genes reflect a mixture of immune cells that is dominated by T cells. T cells react to specific threats to the body's health. In contrast, the poor prognosis signature genes reflect a different group of immune cells dominated by macrophages and/or dendritic cells--which react to nonspecific threats--rather than T cells.

The two signature model allowed NCI scientists to divide patients into four equal groups with disparate average survival rates of 3.9, 10.8, 11.1, and 13.6 years. For the 75 percent of patients with survival rates 10 years or longer, "watchful waiting is appropriate," Staudt said. "These patients would benefit from knowing that they may not need treatment for quite some time. On the other hand, those patients in the group with the lowest survival rate should be considered for newer treatments and clinical trials," added Staudt.

The fact that the most predictive signatures came from immune cells suggests an important interplay between the host immune system and malignant cells in follicular lymphoma. "One possibility is that the immune cells with the good-prognosis signature are attacking the lymphoma and keeping it in check," Staudt speculated. "Another possibility is that these immune cells may provide signals that encourage the cancer cells not to leave the lymph node, preventing or delaying the spread of the cancer," he added. Knowing more about the signals that may delay the spread of follicular lymphoma could provide new therapeutic targets.