Studies Show SNPs Useful in Predicting Toxicity

Drug toxicity is an inherent problem in treating cancer, but recent advances in pharmacogenomics have provided a unique opportunity to be able to identify patients who may be more susceptible to toxicity. Although there has been a renaissance in drugs available for the treatment of renal cancer, these don’t come without problems.

Ram Ganapathi, PhD, Director of the Clinical Pharmacology Program at the Taussig Cancer Institute, with his team in the Department of Translational Hematology and Oncology, are focused on identifying SNPs that predispose patients to toxicity, particularly hypertension following treatment with the angiogenesis inhibitor sunitinib.

“This drug has been extremely valuable because it has made remarkable inroads in managing patients with kidney cancer,” says Dr. Ganapathi. “But hypertension is a serious problem for patients treated with sunitinib.”

Last year, Dr. Ganapathi’s team studied SNPs that led to amino acid changes in key proteins that might predict for toxicity, and came up with a panel of 23 genes from an array that included 13,000 different genes. Then, using results from a study from Indiana University of a different angiogenesis inhibitor, they retrospectively screened 64 patients to evaluate the association among vascular endothelial growth factor (VEGF) SNPs and the development of hypertension in metastatic renal cell carcinoma patients receiving sunitinib.

“What we were able to determine is that one polymorphism clearly predicted for hypertension
in this group,” says Dr. Ganapathi. The findings recently were shared in an oral presentation at the American Society of Clinical Oncology (ASCO) by Jenny Kim, MD, a clinical fellow in the Department of Hematology and Medical Oncology.

Next steps include trying to determine whether this polymorphism can predict toxicity with other drugs used in the treatment of kidney cancer; and whether the information can be used to determine dosing to reduce toxicity.

“Our goal is to uncover distinct signatures that could be used to develop personalized treatment to improve efficacy and, more importantly, to reduce toxicity,” says Dr. Ganapathi. “Addressing toxicity is so important to quality of life. We know this disease is a curse. We don’t need to make it worse. At Cleveland Clinic, we are at the leading edge of developing the strategies needed to personalize treatment.”

Dr. Ganapathi’s program is built on the strong belief that rational and effective treatment of cancer requires a comprehensive understanding of the biology of the tumor being treated, as well as the mechanisms of action and pathways that regulate resistance to anti-cancer drugs. The lab has been supported by the National Cancer Institute and the National Institutes of Health for more than 25 years.

“We have the resources of patients and excellent clinicians to do this kind of array work, which is
not available everywhere,” he says. “We’re now in a position to use them intelligently.”