Grant: Operating Grant - PA: Drug Safety and Effectiveness (bridge funding)

Vincristine is one of the most effective and widely used medications for the treatment of cancer. However, the clinical utility of vincristine is significantly limited by a debilitating and potentially life-threatening adverse drug reaction (ADR). In children, severe or life-threatening vincristine-induced damage to nerves (neurotoxicity) occurs in 13-16% of patients. Patients suffer severe pain in extremities, loss of mobility, delayed cancer treatment, and in some cases, fatal airway obstruction (vocal cord paralysis) or bowel perforation. Currently, there is no way to predict which patients will develop this ADR, and there are no effective treatments other than controlling pain. Importantly, the levels of vincristine in the blood correlate with the neurotoxicity; however, in children that receive similar doses, blood levels can vary up to 30-fold. We hypothesize that these differences are due to variants in genes encoding enzymes that control how vincristine is metabolized or transported in the body that determine an individual's susceptibility to this ADR. We propose to identify these gene variants by testing DNA samples from patients who have developed serious vincristine ADRs and compare them to control patients that have received similar doses of vincristine without neurotoxicity. In a pilot study of 140 pediatric patients, we have already identified gene variants that are highly associated with vincristine-induced neurotoxicity. We now plan to test 9,214 genetic variations in 1,350 drug metabolism and toxicity genes in a new independent cohort of 422 patients to replicate the previous findings and additionally, identify novel associated gene variants. Preliminary results are promising as key gene variants are indeed replicated in the new cohort. This study is a critical next step towards developing a life-saving tool to predict in whom the risk of developing vincristine-neurotoxicity is greatest, to reduce the occurrence and severity of this ADR.