RxPG News : Liver Cancer

Thalidomide may help as adjuvant therapy for hepatocellular carcinoma

Sat, 02 Apr 2011 17:57:25 PST

( from http://www.rxpgnews.com ) Thalidomide has shown potential to be used as the first adjuvant therapy for hepatocellular carcinoma (HCC), according to data presented at the International Liver Congress 2011.

A new study found thalidomide gave HCC patients who had undergone grossly curative resection surgical removal of the cancerous part of the liver double the two-year disease free survival rate (65%) compared to placebo (33%).

However, the study did find that the two-year overall survival rate was comparable between patients treated with thalidomide and patients given placebo – 84.2% and 85.7% respectively.

Daniele Prati, EASL's Scientific Committee Member and Press Committee Chairman, commented: "Current options for adjuvant therapy in HCC are very limited and clinical trial results have been disappointing. Thalidomide has already been proven to work well in a number of other areas and this study shows it could potentially benefit HCC patients who are particularly difficult to treat. Overall, it is important to continue research in evaluating adjuvant therapy in HCC."

Surgery is the main form of treatment for HCC, but is only possible for a small proportion of those afflicted. Even after curative resection, recurrence is common and is the main cause of death. Adjuvant therapy that is, chemotherapy after surgery – is thus attempted to try to improve outcomes.

The study is promising because there is currently no adjuvant therapy for HCC patients following curative resection.

Indeed, the most up-to-date Cochrane Review of adjuvant therapies for HCC (conducted prior to this thalidomide study) found insufficient evidence to show that previously investigated adjuvant therapies increased survival for HCC, and only limited evidence to suggest that adjuvant therapy was useful in disease-free survival.

In the double-blind, placebo controlled, randomized, comparative phase-II study, 42 patients were given 200mg per day oral dose of thalidomide (Arm A, 21 patients) or 200mg per day oral dose of placebo (Arm B, 21 patients). Patients started treatment within 6 weeks of complete tumor resection and carried on treatment for 12 months, or until they encountered disease recurrence, intolerably toxicity, or withdrew consent. Overall, thalidomide showed a good tolerability profile.

Thalidomide is currently approved by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) in the US for the treatment of multiple myeloma (a cancer of the bone marrow).

Chlorophyll limits the absorption of the carcinogen aflatoxin

Wed, 30 Dec 2009 12:52:29 PST

( from http://www.rxpgnews.com ) A new study has found that chlorophyll and its derivative chlorophyllin are effective in limiting the absorption of aflatoxin in humans. Aflatoxin is produced by a fungus that is a contaminant of grains including corn, peanuts and soybeans; it is known to cause liver cancer – and can work in concert with other health concerns, such as hepatitis.

Levels of aflatoxin are carefully regulated in the United States, but are often found in the food supplies of developing nations, especially those with poor storage facilities.

OSU scientist George Bailey, a distinguished professor of environmental and molecular toxicology, pioneered studies of aflatoxin in China, where he found that in one region, one out of every 10 adults died from liver cancer.

But what has the science world particularly intrigued with this follow-up study is the methodology used by the researchers – a new "Phase 0" approach that safely tests low levels of carcinogens in human volunteers to measure the total aflatoxin exposure and to determine the effect of dietary chlorophlls on reducing this exposure.

Results of the study were just published in the journal Cancer Prevention Research.

Bailey and several other researchers, including lead author Carole Jubert, were part of the recent study. The journal also included a perspective written by a pair of Johns Hopkins researchers – Thomas Kensler and John Groopman – who praise the methodology and suggest that these Phase 0 "microdosing" studies should be expanded.

They wrote: "…microdosing studies with carcinogens have the potential to provide important insights into chemopreventive interventions and to enhance the overall clinical development and safety evaluation of preventive agents."

The Phase 0 study "…may open the door for all kinds of new research," said Jubert, a former researcher in Bailey's lab at OSU's Linus Pauling Institute. Jubert now works for Life Microsystems, an OSU spinoff company that hopes to continue work with natural products grown in Oregon, including pure chlorophylls.

"The technology is not particularly difficult," she added. "It's just a novel approach to evaluate toxin exposure in humans."

In their study, Jubert and her colleagues gave very low doses of aflatoxin labeled with carbon-14 isotopes as a tracer to four human volunteers. They then gave the volunteers the same doses of aflatoxin along with doses of either chlorophyll or chlorophyllin, which previously had been shown to reduce carcinogen bioavailability in trout and rats. Using an accelerator mass spectrometer, they measured the rate of aflaxtoxin bioavailability. This technique is extremely sensitive, the researchers say, allowing measurement of minute amounts of any labeled compound.

Their research revealed rapid absorption of aflatoxin, which was significantly limited after the chlorophyll and chlorophyllin treatments.

"The beauty of this kind of 'Phase 0' study is the use of ultra-sensitive technology and 'microdoses' of environmental carcinogens to study toxicokinetics within the human body," said John Mata, an OSU pharmacologist and second author on the study. "These measurements can be important because they allow us to better design future studies to understand the effects of dietary constituents on cancer risk.

"In this case, clearly the results merit further study," Mata added. "We showed that aflatoxin is absorbed quite rapidly and that chlorophyll and chlorophyllin have an ameliorating effect, preventing the toxin from getting into the bloodstream. Further studies can more precisely explore the interactions, as well as dosage levels."

Jubert and Mata also have tested the feasibility of using similar technology on human exposure to other toxins, including smokers who ingest carcinogens through cigarette smoke.

Mata, a professor in OSU's College of Veterinary Medicine, is a pharmacologist who previously worked in the drug industry. He said Phase 1 studies are designed to see if a compound is safe; Phase 2 expands the scope of the project, and Phase 3 looks at the compounds' efficacy. Phase 0 represents a new concept – a way to measure the kinetics of a drug by using extremely small doses that pose little risk to the volunteers.

In this case, the amount of radiation given the human volunteers was equal to that you would encounter from a one-hour airplane ride; the level of aflatoxin administered was 1/30th the amount the Food and Drug Administration allows in a peanut butter sandwich.

Sunitinib slows tumor growth and metastasis in hepatocellular carcinoma

Mon, 14 Apr 2008 14:01:16 PST

( from http://www.rxpgnews.com ) Treatment with sunitinib slows tumor growth and reduces the risk of metastasis in patients with hepatocellular carcinoma, an aggressive cancer of the liver, researchers report.

“Patients with this type of liver cancer have a very poor prognosis and the only currently available therapy is sorafenib. This study shows that we may be able to effectively use sunitinib with manageable side effects,” said Andrew X. Zhu, M.D., Ph.D., director of liver cancer research at Massachusetts General Hospital Cancer Center. “Giving these patients more options would have a significant impact.”

Hepatocellular carcinoma is a cancer that relies heavily on blood vessels for growth; sunitinib controls the growth of blood vessels and could therefore potentially play an important role for treatment, Zhu says.

Researchers enrolled 34 patients with advanced liver cancer and gave them 37.5 mg sunitinib daily on a standard four weeks on, two weeks off regimen. Sunitinib is a small molecule tyrosine kinase inhibitor that targets multiple receptors, including VEGFR2, c-Kit and FLT3. These receptors may be present in cancer cells as well as in endothelial and immune cells.

By 12 weeks, one patient had a partial response and 17 patients had stable disease. The median progression-free survival was four months and the median overall survival was 10 months.

“Results are still preliminary, but there is clear evidence of an anti-tumor activity in these patients,” Zhu said.

Researchers also measured changes in tumor vascular permeability using MRI, because the abnormally increased leakage of plasma from blood vessels in tumors is causally related to pathways blocked by sunitinib. They found that permeability decreased after treatment with sunitinib by 40 percent compared to measures taken at the start of the study.

Circulating progenitor cells, a potential measure of the risk of cancer spread, also were reduced with sunitinib treatment, Zhu says, noting that an increase in circulating progenitor cells during treatment appears to be associated with significantly increased mortality.

Researchers report that the patients tolerated the sunitinib treatment. High levels of SGOT and SGPT liver enzymes were noted in 18 percent and 9 percent of patients, respectively. Blood disorders such as neutropenia (12 percent of patients), lymphopenia (15 percent) thrombocytopenia (12 percent) and hyperbilirubinemia (6 percent) also occurred at low rates. Fatigue was observed in 9 percent of patients and hand-foot syndrome in 6 percent of patients.

Combined stenting and photodynamic therapy may improve survival rates in liver cancer

Tue, 11 Mar 2008 15:40:58 PST

( from http://www.rxpgnews.com ) A combined therapeutic approach of stenting and photodynamic therapy may improve survival rates for patients suffering from advanced liver bile duct cancer, according to a study published this month in Clinical Gastroenterology and Hepatology, the official journal of the American Gastroenterological Association (AGA) Institute.

Researchers in the study found that while stenting can help reinforce the bile duct to increase liver functionality, the light therapy assisted in attacking the cancer cells directly. The combined therapy led to significant reductions in mortality rates in the year following treatment, compared with stenting treatment alone.

“This is a very aggressive disease that we’re fighting, as most patients are diagnosed when we can only offer palliative care,” said Michel Kahaleh, MD, of the University of Virginia and lead investigator of the study. “What we found in this study is that combining therapies that fight the disease and help improve liver functionality can help extend the survival rates for these patients.”

In this study, 48 patients were treated for advanced cholangiocarcinoma over a five year period. Nineteen were treated with photodynamic therapy (PDT) and stents, while 29 patients were treated with biliary stents alone. In the group receiving combined therapy, the photodynamic agent (porfimer sodium, a commonly used agent) was injected and activated, and plastic stents were inserted. PDT was repeated every three months, at which time all stents were replaced. If the team found blockages or shifting, stents were exchanged earlier to maintain optimal decompression.

The group treated with stenting and PDT showed improved survival rates compared to the stent-only group (16.2 months vs. 7.4 months). Mortality in the PDT group at three, six and 12 months was 0, 16 and 56 percent respectively, while the corresponding mortality in the stent group was 28, 52 and 82 percent respectively. The difference between the two groups was significant at three and six months, but not at 12 months. Upon further analysis, the team found that only the number of ERCP procedures and number of PDT sessions were significant in determining survival. In both groups, serum bilirubin was successfully reduced.

PDT is an evolving therapy that involves administering a photosensitizing agent and activating it using light illumination of a specific wavelength, which kills the targeted cells. PDT is thought to destroy cancer and neovascular cells and reduce tumor mass, and in earlier prospective trials, PDT was associated with a significant reduction in bilirubin (a red blood cell byproduct excreted in liver bile) and increased survival compared to historical data.

“While we are pleased with the results of the study, we need to better understand if the effect is attributable primarily to the photodynamic therapy or to the number of ERCP sessions,” said Dr. Kahaleh.

Adverse events specific to PDT included three patients with skin phototoxicity requiring topical therapy. Complications in the stent-only group included patients developing cholangitis after therapy with two patients dying as a consequence. Post ERCP pancreatitis was observed in four patients and duodenal perforation in one. Other adverse events in the stent group included a liver abscess (1), perforation (1) and non-St elevation myocardial infarction, or heart attack (2). In the PDT group, seven patients (37 percent) developed cholangitis treated with antibiotics alone. No patients had contraindications to photodynamic therapy contrast agents, and all patients received prophylactic antibiotics prior to the procedures.

Analyses were performed to detect predictors of survival, including MELD score (Model for End-stage Liver Disease, the extent of the disease), age, treatment by chemotherapy or radiation, and number of ERCP procedures and PDT sessions. Successful therapy was defined by relief of cholangitis (infection caused by biliary blockage), jaundice and pruritis (itching) with a decrease of bilirubin to less than 75 percent of the pre-treatment value within 30 days.

Cholangiocarcinoma (cancer of the liver’s bile ducts) is the second most common liver cancer and is associated with significant morbidity and mortality, diagnosed in about 2,000 new cases every year. The majority of patients (almost 80 percent) are diagnosed when surgery is no longer an option due to the extent of the disease, with most surviving up to three months without intervention or four to six months with decompression treatment, which helps maintain the function of the liver by opening the bile ducts.

Treatment for the disease has evolved from surgery to endoscopic management, which involves placing a plastic stent in the bile duct to manage flow and control the cancerous growth (ERCP). It has become a standard of care to manage jaundice and prevent cholestasis (blockage of the bile duct), with less morbidity and mortality than that associated with surgery. However, the efficacy of stenting is limited because they cannot independently attack the tumor cells.

Percutaneous radiofrequency ablation of liver tumors prove safe and effective

Sat, 05 May 2007 02:14:26 PST

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

The study showed that the percutaneous approach is better tolerated by the patients, with significantly less post-procedural pain.

Percutaneous imaging guided radiofrequency ablation (RFA) of hepatocellular carcinoma is a safe and effective technique, with benefits such as reduced post-procedural pain and length of hospital stay, according to a study conducted by researchers from Changi General Hospital in Singapore.

Radiofrequency ablation of a liver tumor may be performed in a number of ways, said Hui Seong Teh, MD, lead author of the study. Two commonly used techniques are the percutaneous approach and open surgery. There have been few studies that compare the efficacy of the two methods, Dr. Teh says.

The study showed that the percutaneous approach is better tolerated by the patients, with significantly less post-procedural pain. Based on an objective scoring system, average pain score was 0.1 for patients who underwent the percutaneous technique, compared to 1.4 for those who had ablation performed with open laprotomy. Patients also have a much shorter stay in the hospital if they were treated using the percutaneous method, Dr. Teh says. The average length of stay in hospital was 2 days for patients who had the percutaneous method, compared to 10 days for those who had open RFA. The shorter length of hospital stay allows patients to resume their activity of daily living faster and enable their early return to active economy, says Dr. Teh.

"Our study further revealed an interesting finding in that the approaches used for ablation do not affect the effectiveness of the ablation treatment," Dr. Teh added. "The choice of RFA methods will affect the hospital resources spent on these patients, and will have a significant impact on healthcare cost," he said.

The full results of this study will be presented on Wednesday, May 9, 2007 during the American Roentgen Ray Societyâs annual meeting in Orlando, FL.

Cancer cells metastatic to the liver are a perfect target for gene therapy, study reports

Thu, 15 Feb 2007 03:28:37 PST

( from http://www.rxpgnews.com ) A featured paper in the February 14 issue of Nature Cancer Gene Therapy demonstrates that cancer cells in the liver are excellent targets for gene therapy using adenoviral vectors, based upon a fundamental new understanding of the differences between cancerous and normal liver cells. The findings signal a new way to treat cancers that have spread to the liver, such as metastatic cancers of the colon and breast.

The research team, led by Tony Reid, M.D., Ph.D., of the Moores Cancer Center at University of California, San Diego (UCSD), reports that in normal liver cells there is only one receptor or doorway the vector uses to enter the cell. This doorway is located at the base of normal liver cells, hidden from the blood vessels. The research also demonstrates that in cancerous cells the receptor for adenovirus, called the coxsackie-adenoviral receptor or CAR, is expressed randomly over the surface of the cell and is exposed to the blood vessels.

"Since the receptor is distributed randomly on the surface of tumor cells, the doorway is open for the adenoviral vectors circulating in the blood stream to infect and kill these cells," said Reid, who was at Stanford University when this work was conducted. "At the same time, normal liver cells are protected. These findings may signal a new way to treat any cancer that has spread to the liver."

Reid explained: "We are taking advantage of a fundamental characteristic of cancer cells structural disorganization. The disorganized structure of the cancer cells exposes the receptors so that Onyx-015, the adenoviral vectors used in this study, can readily enter tumor cells. This may be the first time a therapy has been directed against the disorganized nature of cancer cells."

Reid and his colleagues undertook this study following the death of Jesse Gelsinger, a participant in a gene therapy clinical trial at University of Pennsylvania for ornithine transcarbanoylase (OTC) deficiency, a metabolic liver disorder. That case virtually stopped gene therapy research and spawned widespread safety concerns about gene therapy involving the liver.

"At that time, I was treating patients with colon cancer that had spread to the liver using a very similar adenoviral vector administered in exactly the same way direct infusion into the main artery feeding the liver," said Reid, who is now an associate professor of clinical medicine in the UCSD School of Medicine. "We saw virtually no problems with toxicity in 35 study participants who received a total of nearly 200 infusions across several study sites."

So Reid and colleagues carefully re-analyzed the data from the 17 participants from the Stanford site to determine the impact of repeated adenoviral exposure on liver function, and documented that there were no significant problems. While the analysis was not designed to demonstrate impact on disease, it showed that seven of the 17 patients had stable-to-improving disease at the completion of four viral infusions. The researchers then demonstrated that normal liver cells could not be infected with an adenovirus, which led them to investigate where the receptor was located. They found it hiding at the junction between liver cells and proved that it was inaccessible from the blood flow in the liver. From there they showed that cancer cells had lost structural polarity, resulting in random distribution of CAR receptors on their surface, thereby allowing the virus to attach to and infect the tumor cells.

"In the process of proving that liver toxicity is not an issue in gene therapy, we have also shown that cancer cells metastatic to the liver are a perfect target for gene therapy because the cancer cells, but not the normal liver cells, are infected by the adenoviral vector," said Reid. "We also found that other cancer cells, including those from the breast, pancreas and prostate, are readily infected by adenoviral vectors indicating disorganized expression of the CAR receptor in these tumor cells. We believe these findings may have important implications across several types of cancer."

The researchers emphasized that while this study demonstrates that adenoviral vectors can be used to deliver targeted therapies and can be a useful tool for the treatment of cancer, further clinical trials are needed.

Nexavar shown to significantly extend survival for patients with advanced liver cancer

Mon, 12 Feb 2007 09:09:17 PST

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

Nexavar(r) (sorafenib) tablets

Bayer Pharmaceuticals Corporation (NYSE: BAY) and Onyx Pharmaceuticals, Inc. (Nasdaq: ONXX) today announced that an independent data monitoring committee (DMC) has reviewed the safety and efficacy data from the companies' pivotal Phase 3 trial in patients with advanced hepatocellular carcinoma (HCC), or primary liver cancer. Based on this planned interim analysis, the DMC has concluded that the trial met its primary endpoint resulting in superior overall survival (OS) in those patients receiving Nexavar® (sorafenib) tablets versus those patients receiving placebo. The DMC also noted that there was no demonstrated difference in serious adverse event rates between the two treatment arms (Nexavar and placebo). Based on these conclusions, the DMC recommended that the trial be stopped early.

As a result of this recommendation, Bayer and Onyx will stop the trial and allow all patients enrolled in this trial access to Nexavar. Given that there are limited approved systemic therapies for this disease, the companies will continue discussions with health authorities worldwide, including the U.S. Food and Drug Administration (FDA) and European health authorities regarding the next steps in filing for approval for the treatment of HCC. Following these discussions, the companies will proceed to file as rapidly as possible. The two companies also reported that they plan to submit the results from the trial to the American Society of Clinical Oncology (ASCO), for presentation at its annual meeting, June 1-5, 2007.

"The observed superiority in overall survival for Nexavar-treated patients over patients receiving placebo demonstrates the efficacy of Nexavar in advanced primary liver cancer," said Dr. Jordi Bruix, co-principal investigator and Head of the Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clinic Barcelona, Spain.

Dr. Josep M. Llovet, co-principal investigator and Associate Professor of Medicine/Director, HCC Research Program, Division of Liver Diseases, Mount Sinai School of Medicine, New York, and Professor of Research at Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clinic Barcelona added, "These results point to new potential treatment options for those patients suffering from this devastating disease."

Colchicine can delay the development of hepatocellular carcinoma

Mon, 11 Sep 2006 16:22:00 PST

( from http://www.rxpgnews.com ) Colchicine, an anti-inflammatory drug most often used to treat gout, prevented liver cancer in patients with hepatitis virus-related end-stage liver disease, according to a new study. Published in the October 15, 2006 issue of CANCER (http://www.interscience.wiley.com/cancer-newsroom) , a peer-reviewed journal of the American Cancer Society, the study found that over three years of follow-up, patients with viral cirrhosis treated with colchicine were significantly less likely to be diagnosed with hepatocellular carcinoma (HCC) than those who did not receive the treatment, and significantly delayed the onset of HCC in patients who did develop the disease.

HCC is the fifth leading cancer worldwide and causes over 1 million deaths per year. The primary risk factor for HCC is fibrotic liver disease, or cirrhosis. Hepatitis viruses B and C are also major risk factors, as are metabolic diseases that affect the liver. Liver disease has a wide clinical spectrum, from mild abnormal lab results to irreversible fibrosis of the liver. Much of the damage to the liver is caused by inflammation, which can be caused by acute or chronic toxin exposure or infection. Inflammation is also implicated in the progression of HCC.

Colchicine is an anti-inflammatory drug commonly used to treat diseases such as gout and psoriasis. Animal studies have found that it also inhibits fibrosis formation in the liver. However, human trials on patients with liver cirrhosis demonstrated no significant efficacy in liver disease progression. Its effect on HCC prevention and progression has never been studied.

Led by Oscar Arrieta, M.D. of the Instituto Nacional de Cancerología in Mexico City, researchers evaluated colchicine as a drug to prevent HCC in patients with liver cirrhosis. They reviewed data from 186 patients with cirrhosis of the liver due to viral disease, of whom 116 were treated with colchicine.

They found that only about one in ten (9 percent) of patients treated with colchicine developed HCC compared to more than one in four (29 percent) of untreated cirrhotic patients. In addition, if subjects developed HCC, patients who were treated with colchicine developed HCC later than those not treated with the drug. Colchicine chemoprevention delayed the diagnosis of HCC after cirrhosis onset by an average 72 months (222 months compared to 150 months). Furthermore, colchicine-treated patients survived longer than untreated patients.

These findings, according to the authors, "demonstrate that colchicine can prevent the development of HCC, independently from other factors such as age, platelet count, alpha-FP and transaminase levels."

Study implicates two human genes in liver cancer

Thu, 29 Jun 2006 02:40:00 PST

( from http://www.rxpgnews.com ) By generating tumors in laboratory mice that mimic human liver cancer and by comparing the DNA of mouse and human tumors, researchers at Cold Spring Harbor Laboratory have identified two genes that are likely to play a role in the third leading cause of human cancer deaths. The study also establishes an efficient and adaptable method for exploring the biology of liver cancer, for validating potential therapeutic targets, and for testing new treatments.

"There has been a long search for animal models that could be predictive of the genes involved in human cancers. These researchers have taken a large step forward in this search and are on a clear path to proving that well-designed animal models can precisely reflect the events observed in human cancers," said Arnold J. Levine of The Institute for Advanced Studies, who was not involved in the study.

Liver cancer ("hepatocellular carcinoma" or HCC) is the fifth most frequent neoplasm worldwide. However, owing to the lack of effective treatment options, it is the third leading cause of cancer deaths.

To gain a better understanding of the molecular causes of HCC, the researchers--led by Scott Lowe of Cold Spring Harbor Laboratory--devised a strategy for genetically engineering liver stem cells, harvested from mouse embryos, and subsequently transplanting the cells into adult mice. Following transplantation (by injection into the spleen), the cells can become part of the recipient mouse's liver.

Depending on the initial, genetically engineered makeup of the liver stem cells, and on genetic alterations that occur spontaneously after they are transplanted, the cells can have a high probability of forming tumors. Scanning the DNA of such tumors has the potential to uncover the relevant spontaneous genetic alterations and reveal the corresponding genes that, when altered, contribute to liver cancer.

In one set of experiments, the scientists engineered the liver stem cells in three ways, two of which were designed to mimic the genetic lesions that are known to occur in human liver and other cancers (namely, deletion of the p53 gene and activation of the Myc gene). A third genetic modification (the insertion of a gene that encodes a fluorescent marker protein) enabled the researchers to visualize the transplanted cells, and their descendants, in the adult mice.

Transplanted cells lacking the p53 gene and bearing an activated version of the Myc gene rapidly gave rise to aggressive, invasive liver tumors. Scanning the DNA of these tumors revealed that a specific segment of mouse chromosome 9 was amplified--or present in excess copies--compared to the DNA of healthy mouse liver cells.

Because this segment of mouse DNA carried several genes, the researchers turned to the human genome to help them narrow down which gene (or genes, as it turned out) was the culprit in liver cancer.

In parallel with their analysis of the mouse liver tumors, the researchers scanned the DNA of human liver and other tumors. Remarkably, they found that a region of human chromosome 11 that is evolutionarily related to the segment of mouse chromosome 9 was amplified in several of the human tumors.

Additional experiments revealed that two genes--Yap and cIAP1--were both consistently overexpressed in both the mouse and human tumors. Thus, when produced at abnormally high levels, proteins encoded by the Yap and cIAP1 genes are likely to contribute significantly to human liver and other cancers.

The study also revealed that whereas producing either the Yap or the cIAP1 protein at an abnormally high level triggers tumor formation in mice, simultaneously overproducing both proteins dramatically accelerates tumor formation. Therefore, these proteins and others in the biochemical pathways they control are attractive candidates for the development of novel cancer therapies.

Skin rash after lapatinib for liver cancer determines survival

Mon, 05 Jun 2006 16:25:00 PST

( from http://www.rxpgnews.com ) In a study of a new chemotherapy drug for liver cancer, researchers found that the development of a skin rash correlated directly with the patient's response to treatment. Patients who developed a rash lived twice as long as those who did not, according to a study led by researchers at the University of Pittsburgh Cancer Institute presented today at the 42nd American Society of Clinical Oncology (ASCO) Annual Meeting in Atlanta.

The study included 57 patients with advanced liver, gallbladder and bile duct cancers who were not candidates for surgery and who received a new agent called lapatinib that prevents two epidermal growth factors receptor (EGFR) pathways from becoming activated in cancer cells. The EGFR pathway has been implicated in the growth and spread of many cancers.

When the researchers evaluated the toxic effects of treatment with lapatinib, they found that twenty of the patients treated had developed a skin rash. Patients who developed the rash lived for an average of 10 months, compared to five months for those patients who did not develop a rash.

"While we don't yet know exactly why this has been reported here and in other studies, it has implications for predicting the growth of cancer and could be a method to identify patients with advanced cancer who would be most likely to respond to this treatment," said Ramesh K. Ramanathan, M.D., principal investigator of the study and associate professor of hematology and oncology at the University of Pittsburgh School of Medicine.

According to the study results, lapatinib was well-tolerated by the patients. Two of the patients with primary liver cancer in the study had a partial response to treatment and the disease was stabilized in an additional 17 patients.

Liquorice compounds could be a key component for liver cancer treatment

Mon, 05 Jun 2006 16:13:00 PST

( from http://www.rxpgnews.com ) Liquorice compounds could be a key component for cheaper, more effective liver cancer treatment, reports Lisa Richards in Chemistry & Industry magazine.

Liver cancer affects over 2,800 people in the UK each year, of which nearly 2,700 die, according to Cancer Research UK. Surgery is the best option, but is unsuitable for most patients, and liver tumours are very resistant to chemotherapy. The American Cancer Society estimates that 18,510 new cases of primary liver cancer and bile duct cancer will be diagnosed in the United States during 2006, and around 16,200 people will die of liver cancer.

Studies in mice by Zhi Yuan and his team at Nankai University, China, revealed that the liquorice compounds, glycerrhetinic acid and glycerrhizic acid, preferentially accumulate in the liver. And when attached to anti-tumours drugs, they are more effective tissue-specific drug carriers than the traditionally used antibodies and oligopeptides (Polymer International DOI 10.1002/pi.2051). 'Our primary results show that they are effective as liver targeting carriers,' says Yuan. Clinical trials are planned for the near future. In addition, glycerrhizic acid is tens of thousands of times cheaper and easier to isolate than the antibodies usually used.

Tim Meyer, Consultant Medical Oncologist at the Royal Free Hospital London agrees, that tissue-specific drugs could potentially provide more effective treatment, because a higher concentration of the drug is delivered to the tumour. This would reduce the dose required and significantly decrease toxic effects on other parts of the body.

Pre-screening before chemotherapy recommended to avoid worst liver damage

Mon, 01 May 2006 00:30:00 PST

( from http://www.rxpgnews.com ) Patients and their physicians should be careful when selecting a chemotherapy drug to treat colorectal cancer that has spread to the liver, say researchers at The University of Texas M. D. Anderson Cancer Center in Houston.

While surgery to remove liver metastases also has proven beneficial, both of the most commonly used chemotherapy drugs to treat these tumors can seriously injure the liver the researchers report in the May 1 issue of the Journal of Clinical Oncology. Furthermore the damage caused to the liver by these preoperative chemotherapy regimens can adversely affects long-term surgical outcomes.

Use of chemotherapy before surgery offers several important benefits, including reducing the size of tumors such that they are more easily removed and, potentially doubling the survival rate.

Results of their 13-year study of 406 patients, treated either at M. D. Anderson or at a hospital in Torino, Italy, found that one drug, irinotecan, produced steatohepatitis (an inflamed "fatty" liver) in 20 percent of patients who used it, and three of those patients later died.

Most of these complications were seen in patients who were overweight or who already had a fatty liver, a condition known as steatosis, says lead author Jean-Nicolas Vauthey, M.D., professor in the Department of Surgical Oncology at M. D. Anderson.

"Most patients who use preoperative chemotherapy when their colorectal cancer spreads to the liver do just fine," Vauthey says. "But this study shows us that we need to screen patients in advance and use the drug that is right for them."

The other most commonly used chemotherapy drug, oxaliplatin, produced sinusoidal dilation (swelling and leaking of blood vessels in the liver) in almost 19 percent of patients who used it, but no deaths were associated with this condition.

"Although such serious complications are comparatively rare, our finding that the choice of chemotherapy matters in outcome will become increasingly important as this surgery becomes more widespread," Vauthey says.

According to the American Cancer Society, more than 146,000 Americans will be diagnosed with cancers of the colon and rectum in 2006. Liver metastasis usually develops from colorectal cancer, and the number of surgeries now performed to remove these tumors is about 10,000 a year "and is expected to double in the near future," Vauthey says.

The study is the first to analyze the association between chemotherapy use before surgery, changes in the function of the liver and postoperative outcome in patients with liver metastases. It is also the first to monitor patient progress for 90 days post surgery. Most surgery outcome studies follow patients for only 30 days, "which is not long enough for these complications to develop," Vauthey says.

Of the 406 patients enrolled in the study, 248 were treated with preoperative chemotherapy and 158 were not. For the entire group, the perioperative complication rate was about 21 percent, and injury to the liver occurred in almost 23 percent. Steatosis was identified in almost nine percent as was high-grade sinusoidal dilation, and steatohepatitis occurred in about eight percent of patients. The investigators further found that while no specific chemotherapy regimen was linked to development of steatosis, oxaliplatin was associated with sinusoidal injury and irinotecan was connected to steatohepatitis when compared to patients who did not receive chemotherapy.

In all, 11 patients died within 90 days of surgery, and six of those deaths occurred in the 92 patients who had hepatic injuries. Five of those patients had steatohepatitis, and one had steatosis. Of the five patients who developed steatohepatitis, three had been treated with irinotecan.

Although steatohepatitis is typically a benign condition, "its presence in patients undergoing chemotherapy treatment may result in failure to regenerate new liver tissue, which can lead to liver disease and failure," Vauthey says.

Researchers further noted that irinotecan was associated with an increased risk of steatohepatitis whether or not a patient was overweight, but that the effect was more pronounced in patients with a higher body mass index (BMI).

Given these findings, researchers recommend patients be screened for BMI and for preexisting steatosis, which chemotherapy can morph into steatohepatitis. Patients in these categories should avoid irinotecan, Vauthey says. "Most patients who use preoperative chemotherapy when their colorectal cancer spreads to the liver do just fine," he says.

While both oxaliplatin and irinotecan are equally effective when combined with fluorouracil, as are other chemotherapy regimens, "this study shows us that we need to screen patients in advance and use the drug that is right for them, Vauthey says "

New technology to detect early liver cancer

Tue, 31 Jan 2006 18:48:00 PST

( from http://www.rxpgnews.com ) Scientists have discovered a technology to detect liver cancer early, which they say could potentially save lives because its treatment is more effective if started early.

Liver cancer or hepatocellular carcinoma is the sixth most common cancer in the world, especially widespread in East Asia.

High-risk groups, such as people with liver cirrhosis, are monitored currently - but tests are not sensitive enough to detect the disease early.

Researchers led by Professor Philip Johnson at the University of Birmingham used sophisticated protein measurement and computer analysis to detect changes characteristic of early liver cancer, reported BBC News.

"Our method was more accurate than the existing liver cancer blood test and will help develop a new test to improve early diagnosis of liver cancer in high risk groups," said Johnson.

It was used to monitor high-risk groups including ultrasound scans and a test for the presence of a single protein in the blood called alpha-fetoprotein.

Enzyme deficiency may contribute to liver cancer

Thu, 28 Jul 2005 19:06:00 PST

( from http://www.rxpgnews.com ) Primary liver cancer is much more likely to take root when a naturally occurring enzyme is in short supply, a team of researchers has found at Mount Sinai Hospital's Samuel Lunenfeld Research Institute.

Using a knockout mouse model, the team has found that the likelihood of hepatoma, or primary liver cancer, increases substantially when half the normal amount of an enzyme called Plk4 is present. Furthermore, 60 per cent of patients with hepatoma were missing one copy of the Plk4 gene in their cancers. The genetic basis for hepatoma has not previously been extensively explored.

The study is published today in the August edition of the prestigious science journal, Nature Genetics.

"Our study indicates that loss of one copy of Plk4 is a major risk factor for primary liver cancer," says Dr. Carol Swallow, a surgical oncologist at Mount Sinai Hospital and an Associate Professor of Surgery at University of Toronto.

"This represents a major advance in our understanding of hepatoma at a molecular level and provides insight into who may be predisposed to this type of cancer genetically."

Dr. Swallow and her co-investigators, Dr. Jim Dennis, Senior Investigator at the SLRI, and Mike Ko, a PhD candidate at the University of Toronto, believe that this finding has important implications for screening and early detection.

The American Cancer Society estimates that there will be 667,000 new cases of liver cancer worldwide in 2005, with 83 per cent of them occurring in developing countries, particularly in Southeast Asia. The disease is also more prevalent in men than it is in women.

"Unlike many common cancers, the incidence of hepatoma is increasing in both developed and developing countries," said Dr. Swallow.

Hepatitis B virus (HBV), hepatocellular carcinoma (HCC) and GSK-3beta

Fri, 22 Jul 2005 01:05:00 PST

( from http://www.rxpgnews.com ) Researchers at The University of Texas M. D. Anderson Cancer Center have uncovered a crucial molecular link between a viral infection and development of a common and fatal form of liver cancer. In the process, they have identified a possible way to treat this disease as well as a number of other cancers.

In findings reported in the journal Molecular Cell, the researchers traced the pathway by which the hepatitis B virus (HBV) leads to development of hepatocellular carcinoma (HCC) and found that it "turns off" an enzyme known as GSK-3ß, which acts to suppress tumor formation as well as inhibit the spread of cancer.

GSK-3ß could prove to be the Achilles heel for liver cancer and other tumors - including breast, colon, kidney and stomach - that use a similar "pathway" to cancer development, the researchers say.

"This study identified a novel mechanism for how hepatitis B primes liver cells to turn cancerous, and what we found has potential relevance for other cancers as well," says the study's lead author Mien-Chie Hung, Ph.D., professor and chair of the Department of Molecular and Cellular Oncology. Hung collaborated with a team of researchers that included scientists from Baylor College of Medicine in Houston, Germany, Taiwan and China.

Infection from HBV is widespread throughout the world, especially in developing nations, and is considered by the World Health Organization (WHO) to be a serious global health problem. The virus, transmitted by blood or body fluids, is up to 100 times more infectious than HIV (human immunodeficiency virus).

Of the 2 billion people who have been infected with HBV, more than 350 million have chronic, or lifelong, infections that put them at high risk of death from cirrhosis of the liver and liver cancer, according to WHO. These diseases kill about one million people worldwide each year.

"HCC accounts for up to 90 percent of all liver cancers, and individuals who carry the hepatitis B virus have a greater than 100-fold increased relative risk of developing HCC," Hung says. "Many researchers have been working to understand how the virus causes this cancer so that potential treatments can be designed."

Scientists have long linked development of HBV to HCC, the most common form of liver cancer. They also believe that this cancer is due to activation of a signaling pathway that includes a protein known as beta catenin. When this protein functions normally, it sits on the outside surface of a cell and helps the cell stick to others like it in a tissue, but when it is found inside the cell's cytoplasm or nucleus, it works to turn on genes involved in cancer development. In the study, 50 percent to 70 percent of all HCC tumors showed an abnormal accumulation of this "oncoprotein" within the cell, Hung says.

What Hung and his team of researchers investigated was just how HBV results in accumulation and activation of the beta catenin oncoprotein. To do that, Qingqing Ding, M.D., a postdoctoral fellow in Hung's lab, initiated experiments to investigate the chain of molecular events that links how HBX, a gene encoded by HBV virus, "upregulates" beta catenin.

What they found is that HBX shuts down GSK-3ß, whose role is to degrade the beta catenin proteins that enter the interior of a cell. Therefore, GSK-3ß functions as a tumor suppressor, and when it is inactive, beta catenin accumulates in the cell cytoplasm and nucleus. They also resolved a puzzle regarding the relationship between GSK-3ß and Erk, a well-known enzyme frequently activated in human cancers. Erk interacts with and phosphorylates GSK-3ß at a specific amino acid residue Thr 43, resulting in degradation and thus inactivation of GSK-3ß.

"When GSK-3ß becomes inactive, then beta catenin is over-expressed," Hung says. "This is important because beta catenin over-expression is found in many cancer types."

But Hung says the investigators found "a way to turn this around." In current research, they have created a super-active mutant of the GSK-3ß gene at amino acid residue Thr 43. By adding this gene into liver cancer cells, over-expression of beta catenin was downregulated, therefore, proliferation of cancer cells will be inhibited. Based on this finding, "we think it may be possible in the near future to develop novel therapeutic approaches for treatment of the aforementioned cancers including development of gene therapy and a small molecule that will activate GSK-3ß," he says.

Expandable Electrodes Useful Alternative to Surgery for Liver Tumors

Mon, 23 May 2005 10:49:00 PST

( from http://www.rxpgnews.com ) The use of expandable electrodes with multiple tips in the treatment of liver tumors by radiofrequency ablation (RFA) is safe and effective, making it a useful alternative to surgery in selected patients, say researchers from the University of Brescia in Italy.

In RFA, electrodes are used to distribute heat-generating electric current to the tumor in order to destroy it.

Expanding electrodes are different from single-tip electrodes in that all the multiple electrode tips of an expanding electrode are active so that heat distribution within the tumor is more homogeneous and a reproducible sphere of ablation is created every time, said Paolo Cabassa, MD, lead researcher on the study.

In addition to the more even distribution of heat, the expanding electrodes include other safety features. The hooks of the electrode are fixed within the liver tissue when deployed so no needle movement is possible during RFA, which makes the procedure safer, and no electrode cooling is required during ablation, making the procedure easier and quicker.

For the study, the researchers, analyzed the results of RFA with expandable electrodes in 68 liver tumors in 59 patients. They found that survival rates for the patients were 94%, 65% and 43% at one, three and five years, respectively, which, according to the authors, is comparable to the best results of surgery. Disease-free rates were 32%, 28% and 18% at one, two and three years, respectively. Only one major complication occurred out of all the RFA procedures, and it was remedied with a transfusion.

RFA is a safe and effective technique to treat liver tumors. Our results show that patients can benefit from this minimally invasive procedure and that it can also be considered as an alternative to surgery in selected cases, said Dr. Cabassa.

Dr. Cabassa presented the full results of the study on May 17 during the American Roentgen Ray Society Annual Meeting in New Orleans, LA.

High levels of immunosuppressant may lead to tumor recurrence

Mon, 25 Apr 2005 22:47:00 PST

( from http://www.rxpgnews.com ) A new study on the incidence of liver cancer after transplant found that high levels of the immunosuppressant cyclosporine favored tumor recurrence and identified blood levels of the drug that should not be exceeded. Lower levels of cyclosporine levels did not affect rejection rates.

The results of this study appear in the May 2005 issue of Liver Transplantation, the official journal of the American Association for the Study of Liver Diseases (AASLD) and the International Liver Transplantation Society (ILTS). The journal is published on behalf of the societies by John Wiley & Sons, Inc. and is available online via Wiley InterScience at http://www.interscience.wiley.com/journal/livertransplantation.

Hepatocellular carcinoma (HCC, a type of liver cancer) occurs frequently in patients with chronic liver disease who are listed for liver transplants. However, the immunosuppressants necessary to prevent rejection can accelerate tumor growth, and the incidence of tumor recurrence is high.

Because of this, strict selection criteria of patients with HCC has limited their access to transplants, yet the role of immunosuprressants in tumor growth has not been well established. In a previous study, the authors demonstrated a close relationship between the amount of cyclosporine and tumor recurrence in liver transplant patients.

The current study further examines this association and identifies possible strategies to avoid it.

Led by Marco Vivarelli of the department of surgery and transplantation at the University of Bologna, Italy, the study examined 70 patients who took cyclosporine as the main immunosuppressant following liver transplants between 1991 and 2002. The cyclosporine dosage was determined by the clinician in charge based on clinical and biochemical indications, but without regard to blood levels achieved by the drug after it was administered. HCC recurred in 7 of the patients between 2 and 40 months after transplant. The researchers found that the absence of recurrence was significantly related to blood levels of cyclosporine, which were higher in patients whose tumors recurred. Other factors, such as recipient sex, underlying liver disease, or the use of cyclosporine with other immunosuppressants or steroids did not affect tumor recurrence.

"We provide here further evidence on the key role of immunosuppression in tumor recurrence after liver transplantation; in particular, we recommend that in those patients transplanted for hepatocellular carcinoma who receive CsAbased [cyclosporine] immunosuppression the exposure to the drug should not exceed the daily blood levels that we identified," the authors state. Since higher and lower levels of cyclosporine did not affect rejection rates, they suggest that minimum dosage levels of the drug can be safely used. In addition, they suggest that immunosuppressive schedules might be tailored to individual patients based on the biology of their tumors, keeping in mind that high-risk patients would probably benefit from keeping cyclosporine levels as low as possible. They conclude that new immunosuppressant drugs shown to have anti-cancer effects are particularly promising for HCC patients.

Radiofrequency (RF) ablation offers an effective first-line treatment for some liver cancer patients who are excluded from surgery

Wed, 16 Feb 2005 15:58:00 PST

( from http://www.rxpgnews.com ) Radiofrequency (RF) ablation offers an effective first-line treatment for some liver cancer patients who are excluded from surgery, according to two studies appearing in the March issue of the journal Radiology.

"I believe that this treatment will soon enter into the guidelines for the clinical management of liver cancer patients," said the first study's lead author, Riccardo Lencioni, M.D., a radiology professor at the University of Pisa in Italy.

Liver cancer is the most common organ malignancy worldwide and generally carries a poor prognosis. Surgical resection removing the cancerous portion of the liver is considered the best hope for a cure. Unfortunately, most patients do not qualify for surgery. Liver transplantations are available for a small number of patients, but organ supply is limited, and tumor progression during the prolonged waiting period results in a high dropout rate. Consequently, RF ablation has emerged as an alternative treatment for inoperable liver cancer and may also be useful as a bridge to liver transplantation.

RF ablation is a minimally invasive procedure where an interventional radiologist uses an image-guided electrode needle to deliver heat directly to tumors, in effect "cooking" them.

Dr. Lencioni and colleagues performed RF ablation on 187 early-stage liver cancer patients with cirrhosis who were not candidates for surgery. People with cirrhosis or Hepatitis B or C virus infections are at increased risk of developing liver cancer. Fewer than 5 percent of liver-cancer patients with cirrhosis qualify for surgical liver resection, and the liver donor shortage limits transplant availability.

"RF ablation was shown to be a safe therapeutic option, with no treatment-induced mortality and a complication rate below 2 percent," Dr. Lencioni said.

Ninety-seven percent of the patients survived one year, 71 percent survived three years, and 48 percent survived five years, which is comparable to results obtained with surgical resection in this type of patient. The results also indicate that RF ablation patient survival is dependent on the type of cirrhosis and number of tumors present.

"The results that we have reported are very promising," Dr. Lencioni said. "However, they can only be obtained when the diagnosis of liver cancer is made at an early, asymptomatic stage. It is of the utmost importance that all patients with chronic hepatitis or cirrhosis who are known to be at risk to develop liver cancer are carefully monitored for timely detection of the emergence of a tumor."

Ablation Success Confirmed by Pathologic Examination

A second study published in the March issue of Radiology further demonstrates the effectiveness of RF ablation to treat liver tumors.

"We have unequivocally demonstrated that RF ablation is highly capable of complete tumor destruction for small liver cancer nodules," said David S.K. Lu, M.D., professor of radiology and director of the image-guided tumor ablation program at the David Geffen School of Medicine at UCLA.

In this study, UCLA researchers used RF ablation to treat 47 liver cancer nodules in 24 patients who were waiting for liver transplantation. After transplantation, pathologic examinations of the diseased livers were performed to retrospectively evaluate RF ablation's effectiveness.

The researchers found that 74 percent of the tumors were successfully treated by ablation. The procedure proved more successful with smaller tumors than with larger tumors, with a success rate of 83 percent when treating tumors 3 centimeters or smaller.

According to Dr. Lu, not all tumors are amenable to such treatments. "It is important to discuss treatment options with a hepatologist or oncologist and to seek consultation with an interventional radiologist experienced in tumor ablation," he said.

Korean Study Examines Interaction of Risk Factors for Liver Cancer Mortality

Thu, 16 Dec 2004 19:21:00 PST

( from http://www.rxpgnews.com ) Cigarette smoking, heavy alcohol consumption, and hepatitis B infection are all independent risk factors for death from liver cancer, but they do not interact synergistically, according to a new study.

Liver cancer is one of the most widespread cancers in the world, particularly in Asia and Africa where hepatitis and aflatoxin exposures are common. Risk factors include chronic alcohol consumption, cigarette smoking, dietary aflatoxin exposure, hepatitis B infection, and hepatic cirrhosis, but there has been limited exploration of the combined effects of these exposures.

Sun Ha Jee, Ph.D., M.H.S., of Yonsei University, in Seoul, Korea, and colleagues conducted a prospective cohort study of more than 1.2 million Korean men and women to assess the independent effects and interactions of three risk factors for liver cancer: cigarette smoking, heavy alcohol consumption, and hepatitis B infection. All three risk factors were independently associated with an increased risk of death from liver cancer, but there was no interaction between them.

Identifying the link between chronic hepatitis B infection and liver cancer may help cancer patients sidestep the poison of chemotherapy

Thu, 16 Dec 2004 18:12:00 PST

( from http://www.rxpgnews.com ) Identifying the link between chronic hepatitis B infection and liver cancer may one day help cancer patients sidestep the poison of chemotherapy, a Purdue University study suggests.

The research group of Ourania M. Andrisani (oo-RAHN-ee-ah an-dri-SAH-nee) has shown that a protein the hepatitis virus instructs chronically infected liver cells to produce - known as the X protein - under certain conditions instructs precancerous infected liver cells to die. The discovery of how the X protein influences liver cell behavior could be harnessed as an anticancer therapy, turning the X protein's presence in the liver to patients' advantage.

"Instead of chemotherapy, drugs that influence the X protein's behavior might become an alternative cancer therapy," said Andrisani, a professor of basic medical sciences in Purdue's School of Veterinary Medicine. "Rather than give a patient chemicals that damage every cell in the body, therapy based on the X protein could potentially target only cancerous cells, slowing their growth."

The research, which Andrisani conducted with first author Wen Horng Wang, and Gérald Gregori and Ronald L. Hullinger, all of Purdue, appears in the current issue of Molecular and Cellular Biology.

Viruses like the hepatitis B virus incorporate their genes into a healthy cell's genetic material. This way, many viruses not only instruct the cell to make proteins necessary to assemble more virus particles, but they also change or deregulate the normal production of proteins by the healthy cell. One of the genes hepatitis B introduces into liver cells is called the X gene, a short sequence of DNA that "expresses," or creates, the X protein - a building block essential for creating hepatitis B. Scientists have suspected the gene and its corresponding protein to be accomplices in cancer development as well.

"The X protein is present in the livers of all chronic hepatitis B patients, and several past studies have implicated it in liver cancer development," Andrisani said. "We decided to look at the effect of the X protein on liver cells in isolation to find out what it was doing to the cells' life cycle."

As a molecular biologist, Andrisani studies how cells receive chemical messages from the body that instruct them to grow, differentiate and die at proper times - actions that are necessary for health in highly specialized bodies like our own. Andrisani's team theorized that the X protein was the chemical messenger that caused the liver cells to behave erratically, putting them out of step with healthy liver tissue.

"To find out what instructions the X protein was feeding the cells, we worked with samples of mouse liver tissue in the lab," she said. "We first took the X gene from hepatitis B and inserted it into liver cell nuclei. Then, after the gene started producing the X protein in the cells, we watched the behavior of these mouse liver samples to see whether they conformed to healthy liver cell life cycles."

To ease observation, they used samples that were only a single layer of cells thick. Observing these modified cells, the team found that the effects of the X gene were a bit complicated.

"The gene does different things to cells at different stages of their lives," Andrisani said. "We found, for example, that liver cells in the beginning of their life cycle will grow vigorously when the X protein is around, but under conditions of stress, it encourages them to die. We have other data, as yet unpublished, that shows the X protein can essentially 'rescue' cells from dying at the appropriate time. Of course, if you see cells growing uncontrollably and refusing to die, then you are looking at the mechanisms of cancer development."

Andrisani likens the X gene to a driver going downhill who doesn't use the car's brakes, allowing the vehicle to accelerate to breakneck speed. But before cells with the X gene can begin proliferating at such an unhealthy rate, it could be possible to counter this behavior with drugs. Andrisani said that it is currently within medicine's power to devise treatments that can eliminate precancerous X-expressing cells, based on their increased tendency to die. Researchers at other institutions also are optimistic about this aspect of the work's implications.

"In fact, some drugs already exist that could help slow the effects of the X protein within the livers of cancer patients," said Spiro Hiotis, a surgeon at New York University who is not affiliated with the study. "While a great deal of further research still needs to be done, Andrisani's team has shown that work with the X gene could someday lead to liver cancer treatments, and managing the gene's effects with drugs could be a viable approach."

This approach could mean that liver cancer could be treated at least in part without chemotherapy, Andrisani said, making for far less overall stress on a patient's body.

"This is what we in the business would call a mechanism-based treatment," she said. "Rather than kill all rapidly-dividing cells in the body - the healthy ones along with the cancerous ones - we would like to target the cancer cells alone. We are taking the next steps toward that goal now."

That next step involves work with live animals instead of tissue samples, she said, and work is now in progress in the labs of Marie-Annick Buendia and Pierre Tiollais of the Louis Pasteur Institute in France.

"In our lab, we are continuing with liver tissue culturing as well," Andrisani added. "We are now trying to work with 3-D cultures of many cell layers, which more closely resemble a normal liver. We hope that with a few years' effort, our work will pay off in the clinic."