RxPG News : Nerve Tissue

Poliovirus Destroyed Neuroblastoma Tumors in Mice

Fri, 23 Mar 2007 03:05:29 PST

( from http://www.rxpgnews.com ) The cause of one notorious childhood disease, poliovirus, could be used to treat the ongoing threat of another childhood disease, neuroblastoma. In the March 15 issue of Cancer Research, researchers from Stony Brook University report that an attenuated -- or non-virulent -- form of poliovirus is effective in obliterating neuroblastoma tumors in mice, even when the mice had been previously vaccinated against the virus.

By its nature, poliovirus destroys the cells it infects in an attempt to replicate copies of itself. When released from the cells it kills, the replicated particles then attack surrounding cells. The Stony Brook researchers took advantage of this viral property by injecting a stable, attenuated strain of poliovirus directly into neuroblastoma tumors transplanted into 12 mice engineered to contract polio. The virus was able to destroy tumors in all 12 mice; however tumors reoccurred in two mice by the end of the 180-day study period.

None of the mice experienced any ill effects from the virus itself. According to the researchers, any viral particles that make it to the bloodstream would be destroyed by antibodies created through poliovirus vaccination. The researchers believe that their findings, if developed to work in humans, could represent a safe, practical means of treating a deadly childhood cancer and possibly many other cancers in adults.

âA tamed poliovirus represents a significant step in finding viral treatments that can kill tumors without harming patients,â said Hidemi Toyoda, M.D., Ph.D., a pediatrician and postdoctoral research fellow in Stony Brookâs Department of Molecular Genetics and Microbiology. âEffectively, we have harnessed a virus that was deadly in children just a few decades ago, namely polio, and used an essential aspect of its nature to destroy a disease that is deadly today.â

Surprisingly, the researchers also discovered that the poliovirus treatment effectively protected the mice against new tumor growth, a significant factor when fighting a disease like neuroblastoma, which is known to reoccur following chemotherapy.

While chemotherapy and radiation therapy are generally effective for some cases of the disease, the prognosis is poor for children with high-risk neuroblastoma.

âNeuroblastoma can be very difficult to treat and the chemotherapies used can lead to health problems later in life,â Toyoda said. âIn combination with conventional therapy, a poliovirus treatment could reduce the exposure of a child to chemotherapy or radiation and lower the risk of harmful side effects.â

To test the effectiveness of poliovirus against cancer tissue, the researchers first had to develop a safe form of the virus. Toyoda and his colleagues work in the laboratory of Stony Brook professor Eckard Wimmer, Ph.D., who in 2002 synthesized poliovirus from its basic chemical components. Based on the properties of the synthetic poliovirus, Wimmer created the highly attenuated virus used in this study by substituting a single nucleotide, located in a functionally important portion of the viral RNA genome called a âspacer regionâ, with an essential regulatory gene removed from elsewhere in the viral genome.

According to Jeronimo Cello, Ph.D., senior author of the Cancer Research paper and research assistant professor at Stony Brook, this engineering feat is like putting a double failsafe into the virus.

âThe engineered poliovirus cannot produce neurovirulent copies of itself if the spacer region remains interrupted,â said Cello. âAnd in the unlikely event that the regulatory gene element is deleted, the virus would not be able to reproduce.â

To test the virusâ ability to destroy neuroblastoma the researchers constructed a transgenic mouse model that allows growth of neuroblastoma cells and carries the human gene for CD155, which codes for the receptor that allows poliovirus to enter cells. The mice were then vaccinated against poliovirus.

Since most humans are immunized against poliovirus, Toyoda and his colleagues needed to know whether such immunization would interfere with the use of the virus in tumor therapy. By injecting the virus directly into the mouse tumors, the researchers demonstrated that it was possible to reach their target and still avoid interacting with the anti-poliovirus antibodies generated by the vaccine.

Not only did the poliovirus prove effective in destroying the tumors, the treatment with virus also seemed to prevent tumors from recurring. Subsequent transplanted tumors were also destroyed, presumably through an enhancement of anti-tumor immune response, say researchers. Since the poliovirus was gone from the system, however, the researchers are unsure of exactly how that immune response occurred.

âThis immunity against neuroblastoma acquired by the animals is still something of a mystery, one that we hope to address in future studies,â Toyoda said. âBut it is an encouraging sign since neuroblastoma are known to relapse quite frequently.â

Coblation SpineWand offers relief for patients with spinal tumors

Sun, 07 May 2006 16:13:37 PST

( from http://www.rxpgnews.com ) A radiologist at the University of California, San Diego (UCSD) School of Medicine has developed a new procedure to treat fractured vertebrae caused by spinal tumors, a procedure that may decrease the risk of complications, which are experienced by 5 to 10% of patients with malignant tumors of the spine.

Wade Wong, D.O.F.A.C.R, UCSD professor of radiology, and San Diego clinician Bassem Georgy, M.D., partially removed spinal tumors from 28 patients before repairing the spine with vertebroplasty a procedure to cement and stabilize damaged vertebrae. He used a technology that utilizes plasma-mediated radiofrequency energy combined with saline solution to gently and precisely remove soft tissue at low temperature minimizing damage to healthy tissue.

"This image-guided procedure guarantees ultimate accuracy," said Wong. It enables us to provide pain relief and improved mobility to patients while minimizing risks that have traditionally limited treatment options for cancer patients."

Wong will present his study on May 6 at the American Society of Interventional and Therapeutic Neuroradiology (ASITN.) He added that some patients in the study who were previously bedridden became much more active after their fractures were repaired using this method, increasing their overall quality of life.

Vertebral compression fractures (VCFs) are common complications of spinal tumors. Approximately 10 percent of the estimated one million VCFs that occur each year in the United States are caused by spinal metastases. Unfortunately, spinal tumors present challenges that traditionally have left many cancer patients with very few treatment options. Open surgery is invasive and involves a long recovery. Traditional vertebroplasty and kyphoplasty two procedures that utilize bone cement to stabilize the fractured vertebrae are also risky when a tumor is present, because the procedures can cause cancerous cells to spread into the blood stream. They also carry a higher risk of bone cement leaking out of the vertebral body into the spinal canal, potentially leading to paralysis.

Wong removed the tumor prior to vertebroplasty on 28 patients using the plasma-mediated procedure commonly known as the "Coblation SpineWand." Following the partial removal of the tumor, bone cement was injected into the cavity created by the process in order to stabilize the fractured bone fragments. The researchers report that all 28 patients treated in the study experienced decreased pain and improved function.

"I never dreamed it would be this successful," said Wong, adding that when first approached the ArthroCare Corporation, manufacturers of the Coblation process, they were skeptical. The device was already in use for other medical applications, such as ear, nose and throat surgery, and arthroscopic applications. "Generally, a cancerous lesion of the spine can eat away at the bone, which can cause a mass in the spinal canal resulting in paralysis or great pain," Wong said.

The process first removes tumor bulk, then delivers cement to strength the vertebrae, which reduces pain.

"It's like creating a cast to a fracture," said Wong, "but in the inside of the body instead of on the outside."

Using the process doesn't preclude other treatments, such as chemo or radiation therapy. Though the process doesn't cure the cancer, it can add to the quality of life for the patient.

"Even in patients with a malignancy, it doesn't mean it's the end of their life. This procedure allows them to resume activities, like walking or even rollerblading, that they enjoyed before," said Wong, adding, "Quality of life is what's key."

Promising neuroblastoma treatment with hu14.18 antibody and gamma-delta-T lymphocytes combination

Thu, 22 Dec 2005 16:34:38 PST

( from http://www.rxpgnews.com ) A new strategy that turns small populations of immune system cells into armies that track down and kill neuroblastoma throughout the body could save the lives of many children each year, according to investigators at St. Jude Children's Research Hospital.

Neuroblastoma is a cancer that arises in immature nerve cells and affects mostly infants and children. The disease often has already spread throughout the body by the time the disease is diagnosed.

The St. Jude strategy represents the successful translation of concepts into a combination therapy that proved effective in laboratory models of neuroblastoma; and that now includes the production of the drugs made to the high standards required for human clinical trials, the researchers say.

Translating this kind of research into the clinic is important because today only 40 percent of children with neuroblastoma can be cured; children who suffer relapses following treatment are virtually incurable. The St. Jude study suggests that the immune system can be manipulated to target cancer cells that have become resistant to traditional chemotherapy.

"This is an extraordinary model for advancing the field of pediatric oncology," said Raymond Barfield, M.D., Ph.D., an assistant member of Hematology-Oncology at St. Jude. "We were able to make rapid progress by doing all the development and production of the antibody on campus. Now we're planning to submit a proposal to the Food and Drug Administration to begin a Phase I trial of this strategy that will permit us to begin exploring ways to use this antibody technique to treat children with neuroblastoma."

The investigational therapy comprises artificial antibodies that tag neuroblastoma cells, immune system cells such as T lymphocytes that attack those tagged cells, and proteins called cytokines that stimulate the T lymphocytes. A report on these preclinical studies appears in the December 1 issue of Clinical Cancer Research.

The St. Jude strategy represents an improvement on a similar technique that showed great promise during clinical trials in Germany and elsewhere, according to Barfield, who is a co-author of the Clinical Cancer Research paper. Prior antibodies caused troublesome side effects, such as fever and pain, which restricted the level of antibody that could be used in the treatment, Barfield said. "However, the antibody we used in our laboratory study appears to be less likely to cause side effects," he said. "That suggests that it could be used in humans at higher levels that may improve the effect of the antibody."

The St. Jude team showed that their treatment could trigger a sustained, highly targeted immune system attack on disseminated (spread over a large area) cancer cells in laboratory models. Moreover, the treatment can be readily transferred to the clinic because each of the three parts of the treatment can be produced at St. Jude at a quality suitable for use in humans, the researchers said.

"Our success with this therapy is especially important because neuroblastoma rapidly spreads through the body, making it difficult to treat," said Mario Otto, M.D., Ph.D., a postdoctoral research fellow at St. Jude. "And many children who are successfully treated suffer a relapse within five years because of the presence of small populations of cancer cells that survive the initial treatment. The question is how to get rid of those few cells that have escaped chemotherapy and can cause relapse. One promising answer is immune therapy that specifically targets these remaining cells." Otto is first author of the paper.

The St. Jude researchers infused into a laboratory model of neuroblastoma an antibody called hu14.18, which sought out and bound to a protein called GD2 on the surface of neuroblastoma cells. They also infused a special type of T lymphocytes called gamma-delta T cells, which attacked the cancer cells that were tagged by hu14.18. In order to stimulate the growth and activity of the gamma-delta cells, the researchers infused an artificial protein called Fc-IL7. IL-7 is a cytokine--a protein that promotes T-lymphocyte survival and proliferation. The Fc protein (immunoglobulin) that is fused to IL-7 slows the process by which the body disposes of this cytokine. The researchers isolated the gamma-delta-T lymphocytes from blood samples obtained from healthy human volunteers.

While the hu14.18 antibody does not directly kill neuroblastoma cells, it does trigger so-called antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC is an arm of the immune system that destroys cells using immune system cells such as "natural killer" cells, and other immune cells, such as such as the gamma-delta-T cells that are part of the St. Jude combination treatment.

"The hu14.18 greatly increased the ability of the gamma-delta-T lymphocytes to trigger ADCC," Otto said. "This antibody was key to the success of our strategy."

Genetic clues guide customized treatment for neuroblastoma

Fri, 25 Nov 2005 06:35:38 PST

( from http://www.rxpgnews.com ) A new study reports that a loss of genes on chromosome 1 or chromosome 11 raises the risk of death from the children's cancer neuroblastoma, even when other indicators seem to point to a lower-risk form of the disease. This research finding will help guide physicians to the most appropriate treatment for the cancer, which strikes the peripheral nervous system. The approach used may also be applied to customizing care for other cancers.

"Identifying more accurate risk levels of this cancer allows doctors to treat aggressive types of the cancer appropriately, while not subjecting children with lower-risk cancer to overtreatment," said study leader John Maris, M.D., of The Children's Hospital of Philadelphia. The study from the Children's Oncology Group, a cooperative research organization of pediatric cancer centers, appears in the November 24 New England Journal of Medicine.

The research team analyzed tumor samples from 915 children with neuroblastoma. Neuroblastoma is the most common cancer in infants, accounting for 10 percent of all pediatric cancers, but its course is not easily predictable. Often occurring as a solid tumor in a child's abdomen or chest, some cases spontaneously resolve even without surgery, while others are particularly aggressive -- resisting initial therapy, or causing a relapse. The more accurately physicians can identify a patient's risk level at the initial evaluation, the better they can customize treatment to each child.

Turning the Tide of Pediatric Cancers Using details of tumor biology to help classify a patient's prognosis a process called risk stratification has received a large boost from the flood of genetic data from the National Genome Project. At the same time, researchers are translating knowledge of molecular events and biological processes into experimental cancer treatments.

As with all science, findings such as the current study of chromosome deletions in neuroblastoma are incremental advances. Those advances occur against the backdrop of a remarkable turnaround: in one generation, survival rates for pediatric cancer have risen from roughly 25 percent in the 1970s to nearly 80 percent today.

One major reason for the dramatic progress in pediatric survival rates is the fact that, over the years, high percentages of children with cancer have participated in clinical trials of new treatments. Today, as researchers work to counteract the most refractory and aggressive cancers, the new treatments are often targeted therapies-- specific agents that attack cancer cells while sparing healthy cells. One such treatment used at Children's Hospital is a compound called MIBG that selectively concentrates in neuroblastoma cells. When bound to a radioactive isotope of iodine and delivered by an I.V. line, the radioactive package kills cancer cells, with low toxicity to healthy tissue.

"These treatments are not cures, but they are bringing us closer to controlling neuroblastoma," says Dr. Maris. "Our goal is to successfully treat the cases that have learned to resist therapy."

Minding P's and Q's in Two Chromosomes Guides Treatment Decisions The current study builds on a foundation of decades of research into neuroblastoma at The Children's Hospital of Philadelphia and other pediatric cancer centers. Pediatric oncologists have known for some time that amplification, an abnormal increase in the number of copies, of a cancer-causing gene called MYCN heralds a high-risk, aggressive form of neuroblastoma. However, some 60 percent of high-risk neuroblastoma tumors do not show MYCN amplification, suggesting that other biological pathways are operating.

Based on previous studies by Dr. Maris and other researchers that identified abnormalities on chromosomes 1 and 11 as contributing to high-risk neuroblastoma, the current research team analyzed gene defects in a large series of neuroblastoma tumors. "We found that loss of genetic material on chromosome bands 1p36 and 11q23 was strongly linked to high-risk neuroblastoma," he said. He added that the survival rate was worse when the loss of material was unbalanced on chromosome 11, occurring on the chromosome's "q" arm but not on its shorter "p" arm.

Scientists call this deletion of one copy of a chromosome "loss of heterozygosity" (LOH). The unbalanced 11q LOH and the 1p36 LOH were independent markers of worse outcome for patients, regardless of other prognostic clues. For instance, unbalanced 11q LOH occurs almost always in tumors not showing amplified copies of the MYCN gene.

"Children known to have MYCN amplification are more likely to already be receiving the most aggressive therapy," said Dr. Maris. "However, it is important to look for 1p36 LOH and unbalanced 11q LOH in children with localized disease without MYCN amplification. Patients having one or both of these deletions may benefit from more intensive early treatment such as chemotherapy. If we can correctly detect risk factors at diagnosis, we can tailor their treatment accordingly."

Based on these findings, the Children's Oncology Group plans to add the status of chromosome arms 1p and 11q to its list of prognostic markers in evaluating children with neuroblastoma. This information will be incorporated into future clinical trials, as researchers analyze new treatments for this pediatric cancer. "As we continue to develop better treatments, we hope to combine those treatments with more refined diagnoses, so we can identify and then treat high-risk cancers earlier, before they can progress or relapse," says Dr. Maris.

The research team will be conducting further work on these particular genetic abnormalities. "Our hope is to identify one or more genes on chromosome arm 11q that are involved in the development of aggressive neuroblastoma, and then use those specific genes as targets for therapy," said lead author Edward F. Attiyeh, M.D., also of The Children's Hospital of Philadelphia.

The researchers also look toward broader implications in their research. "What we have achieved in this pediatric cancer is applicable to other cancers," said Dr. Maris. "This example of molecular medicine is a step in the direction of using powerful genomic technologies to individualizing care."

Methionine Aminopeptidase-2 (MetAP2) - New Therapeutic Target in Neurofibromatosis 1

Wed, 02 Nov 2005 11:55:38 PST

( from http://www.rxpgnews.com ) Researchers studying a mouse model of neurofibromatosis 1 (NF1), a genetic condition that causes childhood brain tumors, have found their second new drug target in a year, a protein called methionine aminopeptidase-2 (MetAP2).

An established drug, fumagillin, is already known to suppress the activity of MetAP2. Researchers at Washington University School of Medicine in St. Louis showed that fumagillin significantly slowed the rapid proliferation of cultured mouse brain cells that resulted from the loss of Nf1, the gene that causes neurofibromatosis 1. Evaluation of the ability of this class of drugs to control brain tumor growth in small animal models is planned.

"This agent and others like it have already been in clinical trials as treatments for other tumors, so if we find that fumagillin inhibits brain tumor growth in preclinical studies, it will be a much smaller leap to using these compounds in patients with NF1," says senior investigator David H. Gutmann, M.D., Ph.D., the Donald O. Schnuck Family Professor of Neurology at Washington University School of Medicine in St. Louis and co-director of the neuro-oncology program at the Siteman Cancer Center.

Neurofibromatosis 1 affects more than 100,000 people in the United States and is one of the most common tumor predisposition syndromes. Gutmann and his colleagues discovered that abnormally high levels of MetAP2 may be a distinguishing characteristic of brain tumors in patients with NF1. Analyses of other similar brain tumors did not reveal the high MetAP2 levels characteristic of tumors caused by NF1.

To identify MetAP2, Gutmann collaborated with Jason D. Weber, Ph.D., assistant professor of medicine and of cellular biology and anatomy at the Washington University Neurofibromatosis Center. The center facilitates multidisciplinary neurofibromatosis research and is dedicated to developing better treatments to improve the lives of patients affected with neurofibromatosis.

Researchers in Gutmann's and Weber's laboratories took samples of cerebrospinal fluid from wild-type mice and a genetically engineered mouse model of NF1. Using a technique called proteomic analysis, they looked at the number of times copies of any given protein were found in the fluid. The goal was to identify proteins whose levels were different in the spinal fluid of the mouse model compared to normal mice.

Gutmann and Weber previously used the genetically engineered mice for a proteomic analysis of astrocytes, the brain cells that often become cancerous in patients with NF1. That led to the finding that proteins in the mammalian target of rapamycin pathway (mTOR) are overactivated, suggesting that mTOR may be a promising target for future chemotherapy for NF1-associated brain tumors.

The new study's results suggest that MetAP2 may be directly regulated by neurofibromin, the protein produced by the Nf1 gene.

Like the mTOR pathway proteins, MetAP2 is normally active in processes that regulate the production of proteins from RNA. Gutmann and Weber plan additional studies to determine how increased MetAP2 expression enables astrocyte growth and brain tumor development.

"The availability of a mouse model of NF1-associated brain tumors allows us to conduct experiments that we could never perform in humans that have already broadened our understanding of the function of the Nf1 gene," Gutmann says. "It's highly likely that these new insights will lead to new treatments for NF1 patients."

No substantial risk of acoustic neuroma with mobile phone use

Sun, 04 Sep 2005 20:16:38 PST

( from http://www.rxpgnews.com ) Scientists from the institute of cancer research in University of Leeds have recently published results from the largest investigation to date into the relationship between mobile phone use and the risk of acoustic neuroma, a nervous system tumour that occurs close to where mobile phones are held to the head.

The study suggests there is no substantial risk of this tumour in the first 10 years after starting mobile phone use. However, an increased risk after longer term use could not be ruled out.

The study published online today in the British Journal of Cancer was conducted in the UK, Denmark, Finland, Norway and Sweden, which are countries where mobile phones were introduced particularly early. Researchers included the University of Leeds reader in paediatric epidemiology Professor Patricia McKinney.

Data were collected from 678 people with acoustic neuroma and 3,553 people who did not have acoustic neuroma ('controls'). Participants were asked in detail about their past mobile phone use (for instance length and frequency of calls, makes and models of phones used, and extent of hands-free use), and also about other factors that might affect their risk of acoustic neuroma.

Acoustic neuromas are benign tumours that grow in the nerve that connects the ear and inner ear to the brain. They often cause loss of hearing in the affected ear and inner ear and a loss of balance. However, acoustic neuromas are usually slow-growing and do not spread to other parts of the body.

The study found no relation between the risk of acoustic neuroma and the number of years for which mobile phones had been used, the time since first use, the total hours of use or the total number of calls, nor were there any relations separately for analogue or digital phone use. There was relatively little information, and the results did not give a clear interpretation, for the risk of tumours after use of a phone for 10 years or longer.

The senior investigator at the institute of cancer research, Professor Anthony Swerdlow, said: There has been public concern about whether there is a link between brain cancer risk and use of mobile phones. The risk of acoustic neuroma is of particular interest in this context because of the proximity of the acoustic nerve to the handset. The results of our study suggest that there is no substantial risk in the first decade after starting use. Whether there are longer-term risks remains unknown, reflecting the fact that this is a relatively recent technology.

Professor Peter Rigby, chief executive of the institute of cancer research said: Mobile phones have only been used widely over the past decade so we wont know the long term effects for many years. However, the results of this multi-country study with such a large number of participants is a great step forward in our understanding of the possible health effects of mobile phones.