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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA139278-02
Application #
7776997
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Jessup, John M
Project Start
2009-03-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
2
Fiscal Year
2010
Total Cost
$171,600
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Geeleher, Paul; Huang, R Stephanie (2017) Exploring the Link between the Germline and Somatic Genome in Cancer. Cancer Discov 7:354-355
Rudin, Shoshana; Marable, Marcus; Huang, R Stephanie (2017) The Promise of Pharmacogenomics in Reducing Toxicity During Acute Lymphoblastic Leukemia Maintenance Treatment. Genomics Proteomics Bioinformatics 15:82-93
Nath, Aritro; Wang, Jacqueline; Stephanie Huang, R (2017) Pharmacogenetics and Pharmacogenomics of Targeted Therapeutics in Chronic Myeloid Leukemia. Mol Diagn Ther 21:621-631
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
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
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
Wang, Fan; Chang, Jeremy T-H; Kao, Chester Jingshiu et al. (2016) High Expression of miR-532-5p, a Tumor Suppressor, Leads to Better Prognosis in Ovarian Cancer Both In Vivo and In Vitro. Mol Cancer Ther 15:1123-31
Geeleher, Paul; Loboda, Andrey; Lenkala, Divya et al. (2015) Predicting Response to Histone Deacetylase Inhibitors Using High-Throughput Genomics. J Natl Cancer Inst 107:
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

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