Genetic Susceptibility and Biomarkers of Platinum-related Toxicities

描述（由申请人提供）：铂化合物是世界上应用最广泛和最成功的细胞毒药物之一，因为它们对多种肿瘤类型都有疗效。每年有超过580万患者被诊断患有结肠癌、直肠癌、子宫颈癌、子宫内膜癌、膀胱癌、胃癌、头颈癌、肺癌、食道癌、胰腺癌、骨肉瘤、卵巢癌和睾丸癌，这些癌症的一线治疗可能包括铂化药物。铂金现在也显示出治疗三阴性乳腺癌的希望。然而，尽管有超过30年的临床使用，没有办法确定有铂毒性风险的患者，他们可以提供替代疗法或减少剂量的方案。对于必须使用铂化药物治疗的患者，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19-77%的患者，其中35-65%发展为耳鸣。30-40%的患者患有长期感觉神经病变。长期顺铂毒性的潜在机制在很大程度上仍然未知。GWAS现在提供了翻译工具，开始描述与这些严重毒性相关的潜在机制，目标是最终制定预防和干预策略。本研究的目的是评估3838例睾丸癌幸存者（TCS）长期铂毒性的遗传易感性。该人群被选为研究铂毒性遗传基础的最佳群体，因为他们在诊断时年龄小，顺铂基础治疗的同质性，治愈率高，治疗后遗症的终身风险。此外，我们研究的方案仍然是标准的护理。我们与该领域的专家一起最近发表了一篇JNCI评论（2010;102:1-17），其中提出了一种新的基于铂的研究策略，重点是首次提供对长期毒性遗传易感性的全面理解。我们的建议来自这些建议。近2年来，研究共同研究者（每天治疗和跟踪TCS的肿瘤学专家）系统地询问了患者，确认他们的人群有很高的积极性参与当前的研究。我们的主要目标是：1；通过多机构的努力，首次建立了一个大型临床特征良好的铂治疗TCS队列，可用于终身随访，以研究长期毒性的遗传基础；2. 鉴定与顺铂长期耳毒性和神经毒性相关的snp；和3。确定并验证通过顺铂细胞易感性研究确定的候选snp与临床长期耳毒性和神经毒性的关联程度。本研究的新颖之处在于，它首次全面评估了已知具有重大终身风险的患者对顺铂长期毒性的遗传易感性，并将包括功能研究。我们的转化研究结果可能会影响全球每年诊断出的数百万癌症患者，这些患者的治疗方法可以包括铂，而不仅仅局限于TCS。我们的结果最终将允许识别长期毒性高风险患者，并制定预防和干预策略。1

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