Platinum compounds comprise one of the most widely used and successful groups of cytotoxic drugs worldwide, given their efficacy in a wide spectrum of tumor types. Each year more than 5.8 million patients are diagnosed with cancers of colon, rectum, cervix, endometrium, bladder, stomach, head and neck, lung, esophagus, pancreas, osteosarcoma, ovary, and testis, for which first-line therapy can potentially include platinating agents. Platinum now also shows promise for triple-negative breast cancer. Despite over 30 years of clinical use, however, there are no means to identify patients at risk for platinum toxicity who might be offered alternative therapies, or reduced-dose regimens. For patients whose management must include platinating agents, there are no preventive measures and no treatment for these debilitating toxicities. Long-term ototoxicity affects 19-77% of patients, with 35-65% developing tinnitus. Long-term sensory neuropathies affect 30-40% patients. The underlying mechanisms of long-term cisplatin toxicity remain largely un- known. GWAS now provides translational tools to begin to characterize the underlying mechanisms associated with these serious toxicities, with a goal of eventually developing preventive and interventional strategies. The objective of this proposal is to evaluate genetic susceptibility to long-term platinum toxicity among a well- characterized clinical cohort of 3,838 testicular cancer survivors (TCS). This population was selected as the optimal group in which to study the genetic underpinnings of platinum toxicity because of their young age at diagnosis, homogeneity of cisplatin-based therapy, high cure rate, and lifelong risk of treatment sequelae. Moreover, the regimens that we study remain the standard of care. We along with experts in the field recently published a JNCI Commentary (2010;102:1-17), which set forth a new platinum-based research strategy, with an emphasis on providing for the first time a comprehensive understanding of genetic susceptibility to long-term toxicity. Our proposal derives from these recommendations. For almost 2 years, study co-investigators (expert oncologists who daily treat and follow TCS) have systematically queried patients, confirming that their populations are highly motivated to participate in the current study. Our major goals are: 1. For the first time, and through a multi-institutional effort, to establish a large clinically well-characterized cohort of platinum-treated TCS available for lifelong follow-up to enable study of the genetic underpinnings of long-term toxicities;2. To identify SNPs associated with long-term cisplatin ototoxicity and neurotoxicity;and 3. To determine and validate the extent to which candidate SNPs identified through studies of cellular susceptibility to cisplatin are associated with clinical long-term ototoxicity and neurotoxicity. The novelty of our study is that it comprehensively evaluates for the first time genetic susceptibility to long-term cisplatin toxicity in patients known to be at substantial lifelong risk and will include functional studies. Results from our translational research will potentially impact the millions of patients who are diagnosed annually worldwide with cancers for which therapy can include platinum, not limited to TCS. Our results will eventually permit identification of patients at high risk for long-term toxicity, and the development of preventive and interventional strategies. 1

Public Health Relevance

The public health significance of this proposal resides in the fact that over 12 million people in the U.S. are cancer survivors, with our research targeting underlying mechanisms of toxicities for one of the most widely used group of chemotherapeutic agents. The proposed research is relevant to the NCI's mission in that it responds to priority research areas identified by the NCI Office of Cancer Survivorship, including neurotoxicity, underlying mechanisms associated with treatment sequelae, and interventions to prevent or reduce the impact of long-term toxicities. We also address research gaps identified by the NCI-LAF Report with regard to survivors of adolescent and young adult cancer. Genomics are also a key priority of the NCI Director, with the NCI research agenda in pharmacogenomics recently outlined in the Journal of the National Cancer Institute, emphasizing translational studies, as we propose.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA157823-01A1
Application #
8243401
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Filipski, Kelly
Project Start
2012-09-25
Project End
2017-07-31
Budget Start
2012-09-25
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$1,510,356
Indirect Cost
$251,054
Name
University of Rochester
Department
Radiation-Diagnostic/Oncology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Feldman, Darren R; Ardeshir-Rouhani-Fard, Shirin; Monahan, Patrick et al. (2018) Predicting Cardiovascular Disease Among Testicular Cancer Survivors After Modern Cisplatin-based Chemotherapy: Application of the Framingham Risk Score. Clin Genitourin Cancer 16:e761-e769
Gamazon, Eric R; Segrè, Ayellet V; van de Bunt, Martijn et al. (2018) Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation. Nat Genet 50:956-967
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Kerns, Sarah L; Fung, Chunkit; Monahan, Patrick O et al. (2018) Cumulative Burden of Morbidity Among Testicular Cancer Survivors After Standard Cisplatin-Based Chemotherapy: A Multi-Institutional Study. J Clin Oncol 36:1505-1512
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
Dolan, M Eileen; El Charif, Omar; Wheeler, Heather E et al. (2017) Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer. Clin Cancer Res 23:5757-5768
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
Fung, Chunkit; Sesso, Howard D; Williams, Annalynn M et al. (2017) Multi-Institutional Assessment of Adverse Health Outcomes Among North American Testicular Cancer Survivors After Modern Cisplatin-Based Chemotherapy. J Clin Oncol 35:1211-1222
Wheeler, Heather E; Gamazon, Eric R; Frisina, Robert D et al. (2017) Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity. Clin Cancer Res 23:3325-3333

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