ASCO 2011: Genetic Biomarker Predicts Taxane Drug-Induced Neuropathy

A new study has identified the first genetic biomarkers for taxane-induced peripheral neuropathy, a potentially severe complication of taxane chemotherapy that affects nerves in about one-third of patients with cancer receiving such treatment.

ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine

The American Society of Clinical Oncology (ASCO) today highlighted several studies in a press briefing from among more than 4,000 abstracts publicly posted online at http://www.asco.org in advance of ASCO’s 47th Annual Meeting. An additional 17 plenary, late-breaking and other major studies will be released in on-site press conferences at the Annual Meeting.

The meeting, which is expected to draw approximately 30,000 cancer specialists, will be held June 3-7, 2011, at McCormick Place in Chicago, Illinois. The theme of this year’s meeting is “Patients. Pathways. Progress.”

“This year marks the 40th anniversary of the signing of the National Cancer Act, a law that led to major new investments in cancer research. Every day in our offices, and every year at the ASCO meeting, we see the results of those investments. People with cancer are living longer, with a better quality of life, than ever before,” said George W. Sledge Jr., M.D., President of ASCO, Ballve-Lantero Professor of Oncology and professor of pathology and laboratory medicine at the Indiana University School of Medicine.

“With our growing understanding of the nature of cancer development and behavior, cancer is becoming a chronic disease that a growing number of patients can live with for many years,” said Dr. Sledge. “The studies released today are the latest examples of progress against the disease, from new personalized treatments, to new approaches to screening and prevention.”

New study results involving a genetic marker which can predict taxane drug-induced neuropathy were highlighted today in the ASCO press briefing, as summarized below.

Genetic Biomarker Predicts Taxane-Induced Neuropathy

A new study has identified the first genetic biomarkers for taxane drug-induced peripheral neuropathy, a potentially severe complication of taxane chemotherapy that affects nerves in about one-third of patients with cancer receiving such treatment. The finding may eventually lead to a simple blood test to determine whether a patient is at high risk for neuropathy.

Bryan P. Schneider, M.D., Physician & Researcher, Indiana University Melvin & Bren Simon Cancer Center; Associate Director, Indiana Institute for Personalized Medicine

“If these findings can be replicated, this may allow physicians to know prior to recommending therapy whether the patient is at an inordinate risk for developing taxane-induced neuropathy,” said Bryan P. Schneider, M.D., lead author and a physician/researcher at the Indiana University Melvin and Bren Simon Cancer Center and Associate Director for the Indiana Institute for Personalized Medicine. “This may allow for better counseling, use of alternative drugs or schedules, or omission of taxanes in the appropriate settings. These genetic findings might also provide insight into the mechanism of this side effect and help develop drugs to prevent this toxicity altogether.”

Such damage to the nerves can cause pain and numbness and limit the dose of chemotherapy a patient can receive. While only a few factors seem to predict which patients are likely to get peripheral neuropathy, including a history of diabetes and advanced age, genetic variations may explain why some patients are more sensitive to taxane drugs.

The authors conducted a genome wide association study on 2,204 patients enrolled in an Eastern Cooperative Oncology Group breast cancer clinical trial (E5103) in which all patients received taxane-based chemotherapy, namely paclitaxel (Taxol). The study looked for variations in DNA (deoxyribonucleic acid) called single nucleotide polymorphisms, or SNPs (pronounced “snips”), by evaluating more than 1.2 million SNPs in each patient.  A SNP is a DNA sequence variation which occurs when a single nucleotide — A (adenine), T (thymine), C (cytosine), or G (guanine) — in the genome (or other shared sequence) differs between two individuals, or between paired chromosomes located within the nucleus of an individual’s cells.

With a median follow-up of 15 months, the study identified genetic subgroups that were markedly more likely to develop peripheral neuropathy.

Those who carried two normal nucleotides in the RWDD3 gene had a 27 percent chance of experiencing neuropathy; those who carried one normal nucleotide and one SNP had a 40 percent risk; and those who carried two SNPs had a 60 percent risk.

In contrast, those who carried two normal nucleotides in the TECTA gene had a 29 percent chance of experiencing neuropathy; those who carried one normal nucleotide and one SNP had a 32 percent risk; and those who carried two SNPs had a 57 percent risk.

The study also found that older patients and African Americans were much more likely to have peripheral neuropathy, and further analysis of SNPs in these groups is underway.

The authors plan to continue their work in additional trials to validate these findings and to determine whether a different type or schedule of taxane therapy would result in less neuropathy in the more susceptible genetic groups. The authors also are collaborating with neurobiologists to understand why these genetic variations might make the nerves more sensitive to these drugs.

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Princeton Scientists Find Way To Catalog All That Goes Wrong In A Cancer Cell

A team of Princeton University scientists has produced a systematic listing of the ways a particular cancerous cell has “gone wrong,” giving researchers a powerful tool that eventually could make possible new, more targeted therapies for patients.

A team of Princeton University scientists has produced a systematic listing of the ways a particular cancerous cell has “gone wrong,” giving researchers a powerful tool that eventually could make possible new, more targeted therapies for patients.

Saeed Tavazoie is a professor in the Princeton University Department of Molecular Biology & the Lewis-Sigler Institute for Integrative Genomics

“For a very long time, cancer therapies have been developed by trial and error to essentially kill a broad variety of rapidly dividing cells, good and bad — that’s why they have massive side effects,” said Saeed Tavazoie, a professor in the Department of Molecular Biology and the Lewis-Sigler Institute for Integrative Genomics, who led the research. “The goal of cancer biology is to come up with therapies that are much more rational in terms of attacking the pathways that have been co-opted by cancer cells. The big challenge is to discover these pathways so that we can restore them to their normal state.”

Writing in the Dec. 11 issue of Molecular Cell, Tavazoie, along with his colleagues Hani Goodarzi, a graduate student in molecular biology, and Olivier Elemento, a former postdoctoral researcher in the department, found they were able to systematically categorize and pinpoint the alterations in cancer pathways and to reveal the underlying regulatory code in DNA. Elemento is now on the faculty of Weill Cornell Medical College in New York.

“We are discovering that there are many components inside the cell that can get mutated and give rise to cancer,” Tavazoie said. “Future cancer therapies have to take into account these specific pathways that have been mutated in individual cancers and treat patients specifically for that.”

The researchers developed an algorithm, a problem-solving computer program that sorts through the behavior of each of 20,000 genes operating in a tumor cell. When genes are turned “on,” they activate or “expressproteins that serve as signals, creating different pathways of action. Cancer cells often act in aberrant ways, and the algorithm can detect these subtle changes and track all of them.

“At the present moment, we lump a lot of cancers together and use the same therapy,” Tavazoie said. “In the future, we are aiming to be much more precise about treating the exact processes that were perturbed by the mutations.”

Pathologists presently examining the tumors of sick patients analyze a small set of tumor characteristics in order to determine the diagnostic and prognostic class to which the cells belong. This new method could give practitioners an encyclopedic accounting of the alterations in problem cells, spelling out the nature of the disease in much greater detail.

The algorithm devised by the group scans the DNA sequence of a given cell — its genome — and deciphers which sequences are controlling what pathways and whether any are acting differently from the norm. By deciphering the patterns, the scientists can conjure up the genetic regulatory code that is underlying a particular cancer.

The scientists developed the technique by employing modern methods of systems biology, where researchers seek to understand how components of living systems like cells work together to orchestrate processes, using powerful computers to sort vast arrays of data.

“Part of the promise of genomics and systems biology is the discovery of specific pathways of disease and finding ways to target them precisely,” Tavazoie said. “We have focused on revealing what these pathways are.”

The challenge for others, he said, will be to design specific therapies for such diseases, a process that could take many years. “This is an important first step,” Tavazoie added.

The method ultimately could work for any type of cancer and paves the way for rational approaches to treating a host of other diseases from diabetes to neurological disorders, the scientists said.

The research was funded by the National Human Genome Research Institute of the National Institutes of Health.

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