Genomics for the win against cancer?

TGen and Genomic Health discover genes affecting cancer drug oxaliplatin, publishing paper calling for more research into mechanisms influencing the drug’s activity

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PHOENIX, Ariz.—Suggesting that genomic research could help physicians better target the use of oxaliplatin in treating colorectal cancer patients, the Translational Genomics Research Institute (TGen) and Redwood City, Calif.-based Genomic Health Inc. recently published a paper titled "Functional Genomics Reveals Diverse Cellular Processes that Modulate Tumor Cell Response to Oxaliplatin" for Molecular Cancer Research, one of six peer-reviewed scientific journals published by the Philadelphia-based American Association for Cancer Research. The paper currently appears in the online version of the journal and is pending print publication.

Oxaliplatin is widely used in colon cancer and is used early in the disease process, after surgery in those cancers that are likely to recur. It is also used in advanced disease to slow progression of the cancer when it has become metastatic.

The problem is that a significant percentage of patients suffer serious side effects from the drug, including prolonged damage to the nervous system, "creating an urgent need to identify genes that are responsible for drug sensitivity or resistance, which results in directing therapy to those most likely to benefit," according to the TGen-Genomic Health study.

Neurotoxicity associated with oxaliplatin is most commonly manifested as pain or a loss of sensation in the hands and feet, which can markedly downgrade a patient's quality of life and ability to work. These symptoms are experienced in some form by the majority of patients receiving the drug, and for some the damage is permanent, the TGen and Genomic Health researchers note.

The researchers examined the role of individual cancer genes to influence the sensitivity or resistance of colon cancer cells grown in laboratory culture. An interfering RNA screen of 500 genes—with 2,000 unique siRNA sequences—identified 27 genes that, when silenced, altered the sensitivity of colon tumor cells to oxaliplatin, causing damage to the cancer cells' DNA and inhibiting the cancer cells' ability to reproduce and survive, according to the study.

"These 27 genes, whose loss of function significantly affect the effectiveness of oxaliplatin, may be promising therapeutic biomarkers for oxaliplatin," says Dr. Holly Yin, head of TGen's Cellular Genomics Collaborative Center in Scottsdale, Ariz., and a co-author of the study.

The authors add that their study also shows that diverse gene networks play a role in the ability of the drug to impact colon tumors.

Dr. Robert J. Pelham, a research scientist at Genomic Health and the study's senior author, says their findings indicate there is a need for additional clinical studies on tumor specimens in patients treated with oxaliplatin, adding, "Such future clinical studies could eventually lead to potential clinical applications, where patients could benefit."

The collaborative research effort that led to the study was initiated by Genomic Health, according to the company's chief medical officer, Steve Shak. They approached TGEN because, as Shak says, "They had the assay in place to do the siRNA screen that we wanted to do. Based on our scientific objectives for this study, it made sense to do this particular study with them."

Yin says that Genomic Health approached TGen about the work roughly two years ago, "and they knew we had the tools in-house for the functional genomic screening capacity that they needed." TGen has been doing this kind of genomic work for some five years now, she adds. Although TGen has done similar work with other companies, it was not allowed to publish those findings.

"We hope that this article will help impact clinical outcomes," Yin says. "We wanted to get the information out that to have an impact in the greater research community for R&D, as well as to improve patient care directly."

Colorectal cancer is the third most common type of cancer in the United States, annually diagnosed in more than 146,000 Americans. It also is the third-highest cause of cancer death in the nation, annually killing nearly 50,000 people, affecting men and women in nearly equal numbers.

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