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: 9342670
• 负责人: Lois B. Travis
• 金额: $ 70.52万
• 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 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9342670
• 关键词: ABCG2 gene; Address; Adolescent and Young Adult; Adverse effects; Affect; Age; Alcohol consumption; Alternative Therapies; Area; Bilateral; Biological Assay; Cancer Etiology; Cancer Survivor; Cancer Survivorship; Candidate Disease Gene; Carbamazepine; Cardiovascular Diseases; Cells; Child; Cisplatin; Clinical; Collection; Colon Carcinoma; Cytarabine; Cytotoxic agent; Data; Development; Diagnosis; Diarrhea; Dose; Drug toxicity; Endometrial Carcinoma; Etiology; Future; Gefitinib; Generations; Genetic Markers; Genetic Predisposition to Disease; Genetic Variation; Genetic study; Genomics; Genotype; Glutathione S-Transferase; Goals; HLA-B Antigens; Head Cancer; Human; Impairment; Intervention; Journal of the National Cancer Institute; Late Effects; Literature; Longitudinal Studies; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of esophagus; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of testis; Malignant neoplasm of urinary bladder; Medical; Methods; Mission; Modeling; Neck Cancer; Neuropathy; Oncologist; Ovary; Paclitaxel; Pathway interactions; Patients; Pharmacogenomics; Phenotype; Platinum; Platinum Compounds; Play; Population; Predisposition; Prevention strategy; Preventive measure; Prospective Studies; Public Health; Published Comment; Publishing; Quality of life; Recommendation; Rectal Cancer; Regimen; Reporting; Research; Research Personnel; Research Priority; Risk; Risk Estimate; Role; Sensorineural Hearing Loss; Series; Stevens-Johnson Syndrome; Survivors; TPMT gene; Targeted Research; Testing; Testis; Time; Tinnitus; Toxic effect; Translational Research; Variant; 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; malignant stomach neoplasm; mortality; 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）：铂化合物是全世界使用最广泛、最成功的细胞毒性药物之一，因为它们对多种肿瘤类型都有功效。每年有超过 580 万名患者被诊断患有结肠癌、直肠癌、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，一线治疗可能包括铂剂。铂现在也显示出治疗三阴性乳腺癌的希望。然而，尽管临床使用已超过 30 年，但仍无法识别有铂类毒性风险的患者，可以为他们提供替代疗法或减少剂量的方案。对于必须使用铂剂进行治疗的患者，没有预防措施，也没有针对这些使人衰弱的毒性的治疗方法。 19-77% 的患者会受到长期耳毒性影响，其中 35-65% 会出现耳鸣。 30-40% 的患者患有长期感觉神经病。长期顺铂毒性的潜在机制在很大程度上仍然未知。 GWAS 现在提供转化工具来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。 该提案的目的是评估由 3,838 名睾丸癌幸存者 (TCS) 组成的特征明确的临床队列对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，因为他们诊断时年龄小、顺铂治疗的同质性、治愈率高以及治疗后遗症的终生风险。此外，我们研究的治疗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)，其中提出了一种新的铂基研究策略，重点是首次全面了解长期毒性的遗传易感性。我们的建议源自这些建议。近两年来，研究共同研究者（每天治疗和跟踪 TCS 的肿瘤专家）系统地询问了患者，确认他们的人群参与当前研究的积极性很高。 我们的主要目标是： 1. 通过多机构的努力，首次建立一个大型临床特征良好的铂类治疗 TCS 队列，可用于终身随访，以便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； 3. 确定并验证通过顺铂细胞敏感性研究鉴定出的候选 SNP 与临床长期耳毒性和神经毒性的相关程度。我们研究的新颖之处在于，它首次全面评估了已知存在重大终生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。我们的转化研究结果可能会影响全世界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以包括铂类药物，而不仅限于 TCS。我们的结果最终将有助于识别长期毒性高风险的患者，并制定预防和干预策略。 1