This application addresses broad challenge area (04) Clinical Research and Specific Challenge Topic, 04-GM-101: Personalized Drug Response and Toxicity. Vincristine is active against a wide variety of malignancies and has been shown to substantially improve outcomes. Although vincristine is among the most commonly used anticancer agents, little is known about optimal therapeutic dosing and it is widely recognized that improper dosing can lead to serious side effects or lack of efficacy. Vincristine is associated with highly variable peripheral neuropathy that often necessitates dose reductions, thereby compromising efficacy. Recently published data indicate that vincristine pharmacokinetics may be associated with long-term outcomes in children with acute lymphoblastic leukemia (ALL). Two enzymes (cytochrome P450 (CYP) 3A4 and CYP3A5) metabolize vincristine;but CYP3A5 is up to 10-times more efficient as a catalyst of vincristine metabolism in vitro. Severity of neurotoxicity may be directly related to an individual patient's vincristine exposure. It may be possible to optimize vincristine dosing based on knowledge of genetic polymorphisms in the vinca alkaloid pharmacologic pathway that may alter vincristine disposition thereby affecting the risk of neurotoxicity. The long-range goal of this research is to optimize the use of this critically important drug. The objective of this proposal is to develop a pharmacologic prediction model of vincristine induced neuropathy in pediatric ALL patients. The central hypothesis is that germline variants in candidate genes are associated with vincristine toxicity, pharmacokinetics, and efficacy. We will test this hypothesis through the following specific aims. In specific aim 1 of the proposal we will determine if there are associations between multiple common or functional variants in genes in the vinca alkaloid pathway, vincristine and metabolite concentrations, and vincristine neuropathy in a multicenter population of children with precursor B cell (preB) ALL receiving vincristine. In specific aim 2 we will utilize the data collected in the first aim to develop a pharmacologic model to characterize the associations between pharmacogenetics, pharmacokinetics, carefully characterized vincristine neuropathy and other clinical variables. The third aim is to utilize the model developed in aim 2 to develop improved dosing guidelines for use of vincristine in pediatric ALL patients to minimize neurotoxicity while optimizing efficacy. This will involve enrollment of a single cohort of 175 children with preB ALL enrolled to a multicenter prospective clinical trial. DNA and plasma pharmacokinetics will be collected and patients will be followed throughout their treatment for evidence of vincristine neurotoxicity. Vincristine neurotoxicity will be carefully evaluated using the standard NCI Common Terminology Criteria as well as more specific and sensitive neuropathy assessment tools (validated in adults) modified for use in children to provide a much more carefully characterized phenotype to facilitate the analysis of the genetic association. A second phenotyped population (140 children enrolled to a nearly completed single institution trial of pharmacogenetics of vincristine neurotoxicity) will be used as a validation cohort. We expect that this research will provide important new information regarding the association of genetic variables and vincristine toxicity and pharmacokinetics. The results will be significant because they will address an important gap in knowledge which will provide the basis for subsequent studies aimed at optimization of vincristine dosing for individual patients (utilizing the model developed as part of this proposal) in the treatment of curable pediatric diseases. The funds provided through this Challenge Grant will provide a consortium of four leading academic medical centers with a strong expertise in pediatric oncology, pharmacogenetics, clinimetrics, and clinical trials to acquire additional expertise in pharmacologic modeling. This application will support employment in the state of Indiana, which had 324,178 unemployed in April, 2009, a 10.1 % unemployment rate relative to the US unemployment rate of 8.9%. This is an 89.1% increase in unemployment in the state of Indiana since February 2008. The institutions involved in this project will work together to conduct a rigorous evaluation of pharmacogenetic predictors of vincristine neuropathy in children with preB ALL. At the end of the grant period, we expect to have the tools necessary to provide individualized vincristine dosing recommendations for children with preB ALL. In the future, we plan to build on this knowledge-base for application to other patient groups treated with vincristine to improve dosing for the nearly 40,000 cancer patients who receive this drug every year. PUBLIC HEALTH RELEVANCE: The research with vincristine that we propose is significant because it is expected to provide the knowledge base needed to determine optimal dosing of vincristine for individual pediatric patients, which has a significant potential to improve survival in the treatment of a number of curable cancers. Once the correlation between genetics and vincristine neurotoxicity fully elucidated, it will be possible to individualize vincristine dosing using genetic information to optimize therapeutic efficacy while minimizing toxicity.
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