Platinum drugs are currently used as standard-of-care chemotherapy, often in combination with taxanes, for various cancers including lung cancer- the most common malignancy, and ovarian cancer- the most lethal gynecological malignancy. However, the overall response rate of carboplatin/paclitaxel-based chemotherapy is far from desirable. Drug resistance, inter-patient variation in response and toxicity are major causes of concern. Genetic factors like differential expression and/or activity in key genes due to the presence of polymorphisms may have an impact on treatment outcome and toxicity. Our approach was to use immortalized lymphoblastoid cell lines/LCLs models derived from epithelial ovarian cancer/EOC patients to identify genetic factors associated with response to carboplatin/paclitaxel single-agent and combination treatments followed by the evaluation of these predictive pharmacogenomic markers in EOC and NSCLC patients undergoing Carboplatin/Paclitaxel combination chemotherapy. We performed a comprehensive profiling of in vitro chemo-sensitivity phenotypes in our panel of ~100 EOC-LCLs following treatment with carboplatin/paclitaxel as single agent and in combination. We demonstrated extensive inter-individual variation in drug response (drug-IC50 and area under survival curve/AUC)). Using Chou-Talalay’s Combination index/CI-Isobologram Theorem we observed wide inter-individual variation in CI and dose reduction index/DRI values. To understand the pharmacogenomics of the inter-individual variation in these chemo-sensitivity parameters, we performed identification of polymorphisms within the pharmacokinetic/PK and pharmacodynamic/PD pathway of carboplatin and paclitaxel as well as analysis of gene expression of these pathway genes in the EOC-LCLs followed by genotype-phenotype association study. Our analysis revealed significant association between drug chemo-sensitivity and genetic variations in several key pathway genes. We then conducted comprehensive genome-wide association scans/GWAS of germline genotype of these patient-derived LCLs to discover predictive pharmacogenomic markers of treatment response. Further, we performed a genotype-phenotype correlation analysis in NSCLC patients treated with carboplatin/paclitaxel-based combination chemotherapy to understand the impact of genetic variations within the PK/PD pathways. We found pathway SNPs associated with treatment outcomes/PFS and toxicity/multiple adverse effects following adjusting for clinical prognostic factors in multivariate models. Thus, we could successfully develop in vitro drug response models and identify key pharmacogenomic changes associated with drug response, treatment outcome and toxicity that could be directly correlated with patient clinical responses.
University of Minnesota Ph.D. dissertation. May 2017. Major: Experimental & Clinical Pharmacology. Advisor: JATINDER LAMBA. 1 computer file (PDF); xi, 231 pages.
MITRA GHOSH, TARASWI.
Pharmacogenomics of Chemotherapeutic Agents: Carboplatin and Paclitaxel.
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