Genetic Susceptibility and Biomarkers of Platinum-related Toxicities

铂相关毒性的遗传易感性和生物标志物

• 批准号: 9137615
• 负责人: Lois B. Travis
• 金额: --
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-25 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9137615
• 关键词: ABCG2 gene; Accounting; Address; Adolescent and Young Adult; Adverse effects; Affect; Age; Alcohol consumption; Alternative Therapies; Area; Bilateral; Biological Assay; Bladder; Breast; Cancer Survivor; Cancer Survivorship; Candidate Disease Gene; Carbamazepine; Cardiovascular Diseases; Cells; Cervix Uteri; Child; Cisplatin; Clinical; Collection; Colon Carcinoma; Cytarabine; Cytotoxic agent; Data; Development; Diagnosis; Diarrhea; Dose; Drug toxicity; Endometrium; Esophagus; Future; Gefitinib; Generations; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Variation; Genetic study; Genomics; Genotype; Glutathione; Goals; HLA-B Antigens; Head and neck structure; Human; Impairment; Intervention; Journal of the National Cancer Institute; Late Effects; Literature; Longitudinal Studies; Lung; Malignant Neoplasms; Malignant neoplasm of testis; Medical; Methods; Mission; Modeling; Neuropathy; Oncologist; Ovary; Paclitaxel; Pancreas; Pathway interactions; Patients; Pharmacogenomics; Platinum; Platinum Compounds; Play; Population; Predisposition; Prevention strategy; Preventive measure; Prospective Studies; Public Health; Published Comment; Publishing; Quality of life; Recommendation; Rectum; Regimen; Reporting; Research; Research Personnel; Research Priority; Risk; Risk Estimate; Role; Sensorineural Hearing Loss; Series; Stevens-Johnson Syndrome; Stomach; Survivors; TPMT gene; Targeted Research; Testing; Testis; Time; Tinnitus; Tobacco; Toxic effect; Transferase; Translational Research; Variant; Vital Status; Woman; base; cancer type; chemotherapeutic agent; cohort; cytotoxicity; demographics; diet and exercise; follow-up; genetic variant; genome wide association study; high risk; innovation; insight; liver injury; malignant breast neoplasm; multidisciplinary; neurotoxicity; novel; osteosarcoma; ototoxicity; prevent; sensory neuropathy; standard of care; tool; translational study; triple-negative invasive breast carcinoma; tumor

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

描述（由申请人提供）：铂化合物包括全球使用最广泛和成功的细胞毒性药物组之一，鉴于它们在各种肿瘤类型中的疗效。每年，超过580万患者被诊断出患有结肠，直肠，子宫颈，子宫内膜，膀胱，胃，头颈部，肺，肺，食管，胰腺，骨肉瘤，骨肉瘤，卵巢和睾丸的癌症，其中一线治疗可能会包括粉碎机。白金现在还显示出三阴性乳腺癌的希望。尽管有30多年的临床用途，但是没有手段可以识别出可能会提供替代疗法或减少剂量方案的铂毒性风险的患者。对于管理剂必须包含铂剂的患者，没有预防措施，也没有治疗这些使人衰弱的毒性。长期耳毒性影响了19-77％的患者，其中35-65％的发作性耳鸣。长期感觉神经病会影响30-40％的患者。长期顺铂毒性的基本机制在很大程度上尚不清楚。 GWAS现在提供了翻译工具，以开始表征与这些严重毒性相关的潜在机制，目的是最终制定预防和介入策略。 该提案的目的是评估3,838个睾丸癌幸存者（TCS）的良好特征临床队列中对长期铂毒性的遗传敏感性。该人群被选为研究铂毒性遗传基础的最佳群体，因为它们的诊断年龄很小，基于顺铂的治疗，高治疗率和终身治疗后遗症风险。此外，我们研究的方案仍然是护理标准。我们与该领域的专家最近发表了JNCI评论（2010; 102：1-17），该评论制定了新的基于铂金的研究策略，并重点是首次提供对长期毒性遗传易感性的全面了解。我们的建议来自这些建议。在将近两年的时间里，研究共同评估者（每天治疗和遵循TCS的专家肿瘤学家）系统地查询了患者，证实他们的人群很有动力参加当前的研究。 我们的主要目标是：1。首次通过多机构的努力，建立了大型临床上良好的铂金治疗TC，可用于终身随访，以实现对长期毒性的遗传基础的研究； 2。确定与长期顺铂耳毒性和神经毒性相关的SNP； 3。确定和验证通过细胞易感性识别顺铂识别的候选SNP与临床长期耳毒性和神经毒性有关。我们研究的新颖性在于，它首次对已知患者的长期顺铂毒性首次对长期顺铂毒性进行了全面评估，并将包括功能研究。我们的翻译研究的结果可能会影响数百万被诊断为全世界诊断为癌症的患者，其中疗法可以包括铂，而不仅限于TC。我们的结果最终将允许确定长期毒性高风险的患者以及预防和介入策略的发展。 1