Most chemotherapeutic drugs affect both tumor and normal cells, are ineffective in a number of patients, and exhibit serious toxicity;hence developing predictive models that identify patients at risk for adverse reactions and/or non-response to chemotherapeutic agents prior to treatment is essential. An objective of this proposal is to take a concerted translational effort to elucidate the underlying cause for the inter-ethnic differences in sensitivity to chemotherapy. In this proposal, we will focus on two classes of cytotoxic agents: platinating agents (cisplatin and carboplatin) and antimetabolites (capecitabine and Ara-C), of which significant inter-ethnic differences in cellular sensitivity have been observed in vitro. Our hypothesis is that there are microRNA (miRNA) expression differences in individuals of African descent compared to individuals of European descent that contribute, at least in part, to the difference in sensitivity to chemotherapy-induced cytotoxicity in these two populations. Our long-term goal is to develop an unbiased genome-wide model to identify germline genetic variants, mRNA or miRNA expression including those in an underserved population, that predict risk for adverse reactions and non-response to chemotherapy. Our hypothesis is that there is a set of germline pharmacogenetic polymorphisms associated with the expression of miRNA that affect chemotherapy-induced cytotoxicity and these polymorphisms exhibit interethnic differences.
Our specific aims are 1) To quantify genome-wide miRNA expression in HapMap lymphoblastoid cell lines (LCLs) and to identify SNPs associated with miRNA expression and chemotherapy-induced cytotoxicity;2) To identify mRNA and miRNA expression signatures that significantly correlate with chemotherapy sensitivity and to compare the miRNA expression chemotherapeutic sensitivity signatures in different ethnic populations;3) To replicate our findings in additional LCLs.
This proposal is intended to better understand how genetic variation contributes to individual sensitivity to chemotherapy. The long term goal is to identify patients, using their genetic make up, that are at risk for toxicities associated with chemotherapy with the intent to reduce their chances of an adverse event.
|Geeleher, Paul; Cox, Nancy J; Huang, R Stephanie (2016) Cancer biomarker discovery is improved by accounting for variability in general levels of drug sensitivity in pre-clinical models. Genome Biol 17:190|
|Morrison, Gladys; Lenkala, Divya; LaCroix, Bonnie et al. (2016) Utility of patient-derived lymphoblastoid cell lines as an ex vivo capecitabine sensitivity prediction model for breast cancer patients. Oncotarget 7:38359-38366|
|French, Juliet D; Johnatty, Sharon E; Lu, Yi et al. (2016) Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer. Oncotarget 7:6353-68|
|Chapin, William J; Lenkala, Divya; Mai, Yifeng et al. (2015) Peripheral blood IRF1 expression as a marker for glucocorticoid sensitivity. Pharmacogenet Genomics 25:126-33|
|Chang, Jeremy T-H; Lee, Yee Ming; Huang, R Stephanie (2015) The impact of the Cancer Genome Atlas on lung cancer. Transl Res 166:568-85|
|Lenkala, Divya; Gamazon, Eric R; LaCroix, Bonnie et al. (2015) MicroRNA biogenesis and cellular proliferation. Transl Res 166:145-51|
|Delaney, Christopher; Frank, Samuel; Huang, R Stephanie (2015) Pharmacogenomics of EGFR-targeted therapies in non-small cell lung cancer: EGFR and beyond. Chin J Cancer 34:149-60|
|Geeleher, Paul; Loboda, Andrey; Lenkala, Divya et al. (2015) Predicting Response to Histone Deacetylase Inhibitors Using High-Throughput Genomics. J Natl Cancer Inst 107:|
|Geeleher, Paul; Cox, Nancy J; Huang, R Stephanie (2014) Clinical drug response can be predicted using baseline gene expression levels and in vitro drug sensitivity in cell lines. Genome Biol 15:R47|
|Rose, Maimon C; Kostyanovskaya, Elina; Huang, R Stephanie (2014) Pharmacogenomics of cisplatin sensitivity in non-small cell lung cancer. Genomics Proteomics Bioinformatics 12:198-209|
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