Pemetrexed is a multitargeted antifolate recently approved for second line therapy of non-small cell lung cancer (NSCLC). The most significant interaction at clinically achievable concentrations is with thymidylate synthase (TYMS), although the drug is known to target at least two other folate dependent enzymes. The goal of this proposal is to identify additional genetic variants that influence pemetrexed-associated toxicity and response by employing a genome-wide, comprehensive approach to test the hypothesis that genetic polymorphisms significantly influence susceptibility to toxicities and response associated with pemetrexed. To this end, lymphoblastoid cell lines, derived from large reference Centre d'Etude du Polymorphisme Humain pedigrees and HapMap (Caucasian, Yoruban, Asian) samples, will be phenotyped for pemetrexed cytotoxicity and apoptosis. Genotypic information is available in the public domain enabling us to apply familial genetic strategies, including linkage analysis, to examine regions in the genome harboring the genetic variants responsible for susceptibility to pemetrexed-induced cytotoxicity and apoptosis. In addition, inter-individual and inter-ethnic variation in pemetrexed-induced cytotoxicity will be compared using the International HapMap samples from populations of African, European and Asian descent. Exon expression array generated in our laboratory will be incorporated to identify genetic variants acting through their effect on baseline gene expression that associate with sensitivity to pemetrexed. Genetic variants identified through this whole genome approach will be validated in a separate sample set of LCLs and by quantitative PCR and siRNA. We will evaluate both novel SNPs and known candidate variants in TYMS, GARFT, DHFR to determine genotypes associated with response or toxicity in an intergroup (NCCTG, CALGB, ECOG, SWOG, NCI-C) study of pemetrexed compared to erlotinib as second line therapy for NSCLC. Our long-term goal is to identify a """"""""pharmacogenetic signature"""""""" that will predict patients with a decreased chance for response or an increased risk for adverse reactions to pemetrexed.
Specific aims are: 1. To determine the genetic contribution of susceptibility to the cytotoxic and apoptotic effects of pemetrexed. 2. To examine baseline and time dependent patterns of expression following pemetrexed treatment. 3. Identify SNPs, through data available from the International HapMap project, associated with both pemetrexed cytotoxicity and gene expression in cell lines derived from Europeans (CEU), Africans (YRI) and Asians (CHB, JPT). 4. To determine if a common polymorphism in TYMS, GARFT, and DHFR, as well as candidate polymorphisms identified in specific aims 1- 3 correlate with response and/or toxicity in advanced NSCLC patients treated with pemetrexed in a multicenter trial.
The objective of this research is to identify lung cancer patients at risk for toxicities or lack of response following treatment with pemetrexed, a chemotherapeutic agent. The project aims to build a model using cell lines to better understand how genetic variation explains differences in patient response to drug. In addition, we will test the results of our model in lung cancer patients treated with pemetrexed. Ultimately, we hope to find predictive markers of pemetrexed response and toxicity.
|Gamazon, Eric R; Trendowski, Matthew R; Wen, Yujia et al. (2018) Gene and MicroRNA Perturbations of Cellular Response to Pemetrexed Implicate Biological Networks and Enable Imputation of Response in Lung Adenocarcinoma. Sci Rep 8:733|
|Wing, Claudia; Komatsu, Masaaki; Delaney, Shannon M et al. (2017) Application of stem cell derived neuronal cells to evaluate neurotoxic chemotherapy. Stem Cell Res 22:79-88|
|Eadon, Michael T; Hause, Ronald J; Stark, Amy L et al. (2017) Genetic Variants Contributing to Colistin Cytotoxicity: Identification of TGIF1 and HOXD10 Using a Population Genomics Approach. Int J Mol Sci 18:|
|Wheeler, Heather E; Wing, Claudia; Delaney, Shannon M et al. (2015) Modeling chemotherapeutic neurotoxicity with human induced pluripotent stem cell-derived neuronal cells. PLoS One 10:e0118020|
|Komatsu, Masaaki; Wheeler, Heather E; Chung, Suyoun et al. (2015) Pharmacoethnicity in Paclitaxel-Induced Sensory Peripheral Neuropathy. Clin Cancer Res 21:4337-46|
|Diouf, Barthelemy; Crews, Kristine R; Lew, Glen et al. (2015) Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia. JAMA 313:815-23|
|Wheeler, Heather E; González-Neira, Anna; Pita, Guillermo et al. (2014) Identification of genetic variants associated with capecitabine-induced hand-foot syndrome through integration of patient and cell line genomic analyses. Pharmacogenet Genomics 24:231-7|
|Pinto, N; Gamazon, E R; Antao, N et al. (2014) Integrating cell-based and clinical genome-wide studies to identify genetic variants contributing to treatment failure in neuroblastoma patients. Clin Pharmacol Ther 95:644-52|
|Stark, Amy L; Hause Jr, Ronald J; Gorsic, Lidija K et al. (2014) Protein quantitative trait loci identify novel candidates modulating cellular response to chemotherapy. PLoS Genet 10:e1004192|
|Wheeler, Heather E; Maitland, Michael L; Dolan, M Eileen et al. (2013) Cancer pharmacogenomics: strategies and challenges. Nat Rev Genet 14:23-34|
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