Paclitaxel is a tubulin-targeting agent used in the treatment of many cancers, including breast, lung, head and neck, and ovarian. Peripheral neuropathy is a common side effect of many chemotherapeutic agents, including paclitaxel, and limits their efficacy in patients. The overall goal of our work is to identify patients at risk for peripheral neuropathy using whole genome preclinical and clinical studies. Epstein-Barr virus transformed lymphoblastoid cell lines (LCLs) have emerged as a promising preclinical model system in the study of the genetics of drug toxicity because the cells provide a cost-effective testing system in which environmental factors such as concomitant medications can be controlled. Most importantly, publicly available genotype and sequencing data is available, to allow for genome-wide association studies between HapMap/1000 Genomes variants and pharmacologic phenotypes measured in the LCLs after drug treatment such as paclitaxel induced growth inhibition and apoptosis. The overall genetic architecture of paclitaxel-induced neuropathy is well captured by the cell-based models as evidenced by significant enrichment of paclitaxel-induced toxicity SNPs from the preclinical model in clinical genome-wide association studies of peripheral neuropathy. We utilized iCell Neurons, which are commercially available cells derived from induced pluripotent stem cells, to study the effects of gene modulation on paclitaxel-induced cell growth inhibition using Cell Titer Glo and on neurite parameters of outgrowth, processes and branching using the ImageXpress Micro system. Through transient knockdown in iCell Neurons of RFX2, a gene identified through clinical and preclinical studies to be associated with paclitaxel neuropathy, sensitivity to paclitaxel increased as measured by a decrease of neurite outgrowth, processes and branching. The ability to identify cancer patients at risk of paclitaxel-induced peripheral neuropathy could influence treatment choice, outcome and quality of life for breast, lung, head and neck, and ovarian cancer patients. This work was supported in part by NIH/NIGMS UO1GM61393.

Citation Format: Heather E. Wheeler, Cristina Rodriguez-Antona, Claudia Wing, Masaaki Komatsu, M. Eileen Dolan. Integration of preclinical and clinical studies to identify pharmacogenetic markers associated with paclitaxel-induced neuropathy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2210. doi:10.1158/1538-7445.AM2013-2210

©2013 American Association for Cancer Research
2013