Genetic Susceptibility and Biomarkers of Platinum-related Toxicities

描述(申请人提供)：铂化合物组成了世界上最广泛使用和最成功的细胞毒性药物之一，因为它们对广泛的肿瘤类型有效。每年有超过580万患者被诊断出患有结肠癌、直肠癌、子宫颈癌、子宫内膜癌、膀胱癌、胃癌、头颈部癌、肺癌、食道癌、胰腺癌、骨肉瘤、卵巢癌和睾丸癌，对于这些癌症，一线治疗可能包括铂类药物。铂现在也显示出治疗三阴性乳腺癌的希望。然而，尽管临床使用了30多年，仍然没有办法识别有铂中毒风险的患者，他们可能会被提供替代疗法或减少剂量的方案。对于其治疗必须包括铂类药物的患者，没有预防措施，也没有针对这些衰弱毒性的治疗。长期的耳毒性影响19-77%的患者，35-65%的患者出现耳鸣。长期的感觉神经病影响30%-40%的患者。顺铂长期毒性的潜在机制在很大程度上仍不清楚。Gwas现在提供了翻译工具，以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。这项建议的目的是评估3838名睾丸癌幸存者(TC)中具有良好特征的临床队列中对长期铂毒性的遗传易感性。这一群体被选为研究铂毒性遗传基础的最佳群体，因为他们确诊时年龄较小，基于顺铂的治疗的同质性，高治愈率，以及治疗后遗症的终身风险。此外，我们研究的养生法仍然是护理的标准。我们最近与该领域的专家一起发表了一篇JNCI评论(2010；102：1-17)，其中提出了一种新的以铂为基础的研究战略，重点是首次全面了解长期毒性的遗传易感性。我们的建议是从这些建议衍生出来的。近两年来，研究联合调查者(每天治疗和跟踪TCS的专家肿瘤学家)系统地询问患者，确认他们的人口高度有动力参与当前的研究。我们的主要目标是：1.首次通过多机构的努力，建立大量临床特征良好的铂治疗TC队列，用于终身随访，以便能够研究长期毒性的遗传基础；2.确定与顺铂长期耳毒性和神经毒性相关的SNPs；以及3.确定和验证通过细胞对顺铂的敏感性研究确定的候选SNPs与临床长期耳毒性和神经毒性相关的程度。我们研究的新颖性在于，它首次全面评估了已知存在巨大终身风险的患者对长期顺铂毒性的遗传易感性，并将包括功能研究。我们转译研究的结果可能会影响全球每年被诊断患有癌症的数百万患者，这些癌症的治疗方法可能包括铂类药物，而不仅仅是TCS。我们的结果最终将有助于识别长期毒性的高危患者，并制定预防和干预策略。1 公共卫生相关性：这项提案的公共卫生意义在于，美国有超过1200万人是癌症幸存者，我们的研究针对的是最广泛使用的化疗药物之一的潜在毒性机制。拟议的研究与NCI的使命相关，因为它回应了NCI癌症生存办公室确定的优先研究领域，包括神经毒性、与治疗后遗症相关的潜在机制，以及预防或减少长期毒性影响的干预措施。我们还解决了NCI-LAF报告中确定的关于青少年和年轻成人癌症幸存者的研究空白。基因组学也是NCI主任的一个关键优先事项，NCI在药物基因组学方面的研究议程最近在《国家癌症研究所杂志》上概述，正如我们建议的那样，强调转译研究。

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.