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Grant Details

Grant Number: 1R01CA157823-01A1 Interpret this number
Primary Investigator: Travis, Lois
Organization: University Of Rochester
Project Title: Genetic Susceptibility and Biomarkers of Platinum-Related Toxicities
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): 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.

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Publications

Application of stem cell derived neuronal cells to evaluate neurotoxic chemotherapy.
Authors: Wing C. , Komatsu M. , Delaney S.M. , Krause M. , Wheeler H.E. , Dolan M.E. .
Source: Stem Cell Research, 2017 Jul; 22, p. 79-88.
EPub date: 2017-06-15 00:00:00.0.
PMID: 28645005
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Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer.
Authors: Dolan M.E. , El Charif O. , Wheeler H.E. , Gamazon E.R. , Ardeshir-Rouhani-Fard S. , Monahan P. , Feldman D.R. , Hamilton R. , Vaughn D.J. , Beard C. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2017-06-13 00:00:00.0; , .
EPub date: 2017-06-13 00:00:00.0.
PMID: 28611204
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Genome-Wide Association Studies of Chemotherapeutic Toxicities: Genomics of Inequality.
Authors: Mapes B. , El Charif O. , Al-Sawwaf S. , Dolan M.E. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2017-04-25 00:00:00.0; , .
EPub date: 2017-04-25 00:00:00.0.
PMID: 28442506
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Multi-Institutional Assessment of Adverse Health Outcomes Among North American Testicular Cancer Survivors After Modern Cisplatin-Based Chemotherapy.
Authors: Fung C. , Sesso H.D. , Williams A.M. , Kerns S.L. , Monahan P. , Abu Zaid M. , Feldman D.R. , Hamilton R.J. , Vaughn D.J. , Beard C.J. , et al. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2017-04-10 00:00:00.0; 35(11), p. 1211-1222.
EPub date: 2017-02-27 00:00:00.0.
PMID: 28240972
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High-Dose Chemotherapy and Autologous Peripheral-Blood Stem-Cell Transplantation for Relapsed Metastatic Germ Cell Tumors: The Indiana University Experience.
Authors: Adra N. , Abonour R. , Althouse S.K. , Albany C. , Hanna N.H. , Einhorn L.H. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2017-04-01 00:00:00.0; 35(10), p. 1096-1102.
EPub date: 2016-11-21 00:00:00.0.
PMID: 27870561
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Variants In Wfs1 And Other Mendelian Deafness Genes Are Associated With Cisplatin-associated Ototoxicity
Authors: Wheeler H.E. , Gamazon E.R. , Frisina R. , Perez-Cervantes C. , El Charif O. , Mapes B. , Fossa S.D. , Feldman D. , Hamilton R. , Vaughn D.J. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2016-12-30 00:00:00.0; , .
PMID: 28039263
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Increased Pancreatic Cancer Risk Following Radiotherapy For Testicular Cancer
Authors: Hauptmann M. , Børge Johannesen T. , Gilbert E.S. , Stovall M. , van Leeuwen F.E. , Rajaraman P. , Smith S.A. , Weathers R.E. , Aleman B.M. , Andersson M. , et al. .
Source: British Journal Of Cancer, 2016-09-27 00:00:00.0; 115(7), p. 901-8.
PMID: 27599043
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Comprehensive Audiometric Analysis Of Hearing Impairment And Tinnitus After Cisplatin-based Chemotherapy In Survivors Of Adult-onset Cancer
Authors: Frisina R.D. , Wheeler H.E. , Fossa S.D. , Kerns S.L. , Fung C. , Sesso H.D. , Monahan P.O. , Feldman D.R. , Hamilton R. , Vaughn D.J. , et al. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2016-08-10 00:00:00.0; 34(23), p. 2712-20.
PMID: 27354478
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Novel genetic predictors of venous thromboembolism risk in African Americans.
Authors: Hernandez W. , Gamazon E.R. , Smithberger E. , O'Brien T.J. , Harralson A.F. , Tuck M. , Barbour A. , Kittles R.A. , Cavallari L.H. , Perera M.A. .
Source: Blood, 2016-04-14 00:00:00.0; 127(15), p. 1923-9.
EPub date: 2016-04-14 00:00:00.0.
PMID: 26888256
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Chemotherapy-Related Chronic Myelogenous Leukemia: A Case Series of Patients With Germ Cell Tumor.
Authors: Adra N. , Sayar H. , Einhorn L.H. .
Source: Jama Oncology, 2016 Mar; 2(3), p. 391-2.
PMID: 26632950
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Chemotherapy-induced peripheral neuropathy: Current status and progress.
Authors: Brewer J.R. , Morrison G. , Dolan M.E. , Fleming G.F. .
Source: Gynecologic Oncology, 2016 Jan; 140(1), p. 176-83.
PMID: 26556766
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Cardiovascular Disease Mortality After Chemotherapy or Surgery for Testicular Nonseminoma: A Population-Based Study.
Authors: Fung C. , Fossa S.D. , Milano M.T. , Sahasrabudhe D.M. , Peterson D.R. , Travis L.B. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2015-10-01 00:00:00.0; 33(28), p. 3105-15.
EPub date: 2015-10-01 00:00:00.0.
PMID: 26240226
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Utilization of sperm banking and barriers to its use in testicular cancer patients.
Authors: Sonnenburg D.W. , Brames M.J. , Case-Eads S. , Einhorn L.H. .
Source: Supportive Care In Cancer : Official Journal Of The Multinational Association Of Supportive Care In Cancer, 2015 Sep; 23(9), p. 2763-8.
PMID: 25680764
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Increased stomach cancer risk following radiotherapy for testicular cancer.
Authors: Hauptmann M. , Fossa S.D. , Stovall M. , van Leeuwen F.E. , Johannesen T.B. , Rajaraman P. , Gilbert E.S. , Smith S.A. , Weathers R.E. , Aleman B.M. , et al. .
Source: British Journal Of Cancer, 2015-01-06 00:00:00.0; 112(1), p. 44-51.
EPub date: 2015-01-06 00:00:00.0.
PMID: 25349972
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Modeling chemotherapeutic neurotoxicity with human induced pluripotent stem cell-derived neuronal cells.
Authors: Wheeler H.E. , Wing C. , Delaney S.M. , Komatsu M. , Dolan M.E. .
Source: Plos One, 2015; 10(2), p. e0118020.
PMID: 25689802
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Testicular cancer: a reflection on 50 years of discovery.
Authors: Hanna N. , Einhorn L.H. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2014-10-01 00:00:00.0; 32(28), p. 3085-92.
EPub date: 2014-10-01 00:00:00.0.
PMID: 25024068
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Chemotherapy-induced peripheral neurotoxicity and ototoxicity: new paradigms for translational genomics.
Authors: Travis L.B. , Fossa S.D. , Sesso H.D. , Frisina R.D. , Herrmann D.N. , Beard C.J. , Feldman D.R. , Pagliaro L.C. , Miller R.C. , Vaughn D.J. , et al. .
Source: Journal Of The National Cancer Institute, 2014-03-12 00:00:00.0; 106(5), .
EPub date: 2014-03-12 00:00:00.0.
PMID: 24623533
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Solid tumors after chemotherapy or surgery for testicular nonseminoma: a population-based study.
Authors: Fung C. , Fossa S.D. , Milano M.T. , Oldenburg J. , Travis L.B. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2013-10-20 00:00:00.0; 31(30), p. 3807-14.
EPub date: 2013-10-20 00:00:00.0.
PMID: 24043737
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Outcomes in stage I testicular seminoma: a population-based study of 9193 patients.
Authors: Beard C.J. , Travis L.B. , Chen M.H. , Arvold N.D. , Nguyen P.L. , Martin N.E. , Kuban D.A. , Ng A.K. , Hoffman K.E. .
Source: Cancer, 2013-08-01 00:00:00.0; 119(15), p. 2771-7.
EPub date: 2013-08-01 00:00:00.0.
PMID: 23633409
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Prognostic factors in patients with poor-risk germ-cell tumors: a retrospective analysis of the Indiana University experience from 1990 to 2014.
Authors: Adra N. , Althouse S.K. , Liu H. , Brames M.J. , Hanna N.H. , Einhorn L.H. , Albany C. .
Source: Annals Of Oncology : Official Journal Of The European Society For Medical Oncology, 2016 05; 27(5), p. 875-9.
EPub date: 2016-02-09 00:00:00.0.
PMID: 26861605
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