SPORE in Bladder Cancer

项目摘要/摘要 肿瘤学社区中有一种明显的兴奋，我们正处于一项重大进展的尖端，如何 治疗膀胱(尿路上皮癌)癌。最近为全面界定基因改变的格局所做的努力 了解它们对药物敏感性的影响，以及令人兴奋的早期结果 免疫靶向策略表明，血液和肿瘤组织的预期分子图谱可能 通过个性化护理改善尿路上皮癌患者的预后。膀胱癌中的MSK孢子 寻求利用最近发起的多中心努力来探索遗传基因的分子基础 敏感性，利用前瞻性的分子特征来指导治疗，并测试 以免疫治疗为基础的联合治疗方法。MSK孢子在膀胱中的整体翻译目标 癌症的目标是：1)开发免疫治疗、化疗、 和研究治疗；2)确定生殖系基因改变，使风险增加 尿路上皮癌的发展；以及3)识别免疫治疗抵抗的机制和发展 提高尿路上皮癌患者免疫治疗反应的联合策略。追寻 为了实现这些目标，我们组建了一个多学科团队，在临床上具有互补的专业知识 尿路上皮癌的管理，遗传风险，分枝杆菌和癌症生物学，癌症遗传学， 分子病理学、生物统计学、计算生物学和多平台数据集成。翻译型 这个孢子的目标将通过四个项目来实现，每个项目都针对不同的临床状况 疾病的演变。项目1将使用预期的分子表征来确定 合作组试验的背景，无论是经尿道电切和化疗，而不需要 膀胱切除术，是治愈DNA损伤反应基因改变的患者并确定新的 化疗敏感性的生物标志物。项目2将鉴定和确定新的生殖系的功能特征 导致遗传易感性增加的变异。项目3将寻求识别和验证肿瘤-以及 以血液为基础的预测生物标记物对全身免疫检查点阻断的反应 一项随机多中心试验中的转移性尿路上皮癌。项目4将寻求确定 卡介苗(BCG)应答的预测生物标志物和卡介苗活性较高的菌株 拉开了未来临床试验的序幕。这些项目中的每一个都将得到生物质学家储存库和 生物统计和生物信息学核心，将协助准备和分析人体组织和 基因组、免疫和临床数据，以及管理核心将确保项目集成。最后， 发展研究项目和职业指导完全融入孢子中，以确保 下一代研究人员准备进一步推进我们加强治疗的长期目标， 减少治疗的发病率，并最终消除这种疾病作为过早死亡的原因。

Project Summary/Abstract There is palpable excitement in the oncology community that we are on the cusp of a major advance in how we treat bladder (urothelial) cancer. Recent efforts to comprehensively define the landscape of genetic alterations in urothelial cancer and to understand their impact on drug sensitivity, as well as the exciting early results with immune targeting strategies suggest that prospective molecular profiling of blood and tumor tissue could improve the outcomes of urothelial cancer patients by personalizing care. This MSK SPORE in Bladder Cancer seeks to leverage recently initiated multicenter efforts to explore the molecular basis of inherited genetic susceptibility, exploit prospective molecular characterization to guide treatment, and to test the efficacy of immunotherapy-based combination approaches. The overall translational aims of the MSK SPORE in Bladder Cancer are to 1) develop predictive biomarkers of response and resistance to immunotherapy, chemotherapy, and investigational treatments; 2) identify germline genetic alterations that confer increased risk for the development of urothelial cancer; and 3) identify mechanisms of immunotherapy resistance and develop combinatorial strategies to enhance immunotherapy response in patients with urothelial cancer. To pursue these aims, we have assembled a multidisciplinary team with complementary expertise in the clinical management of urothelial cancer, inheritable risk, mycobacterial and cancer biology, cancer genetics, molecular pathology, biostatistics, computational biology, and multiplatform data integration. The translational aims of this SPORE will be pursued through four projects, each of which addresses a different clinical state in the evolution of the disease. Project 1 will use prospective molecular characterization to determine, in the context of a cooperative group trial, whether transurethral resection and chemotherapy, without the need for cystectomy, is curative in patients with DNA damage response gene alterations and to identify novel biomarkers of chemotherapy sensitivity. Project 2 will identify and functionally characterize novel germline variants that confer increased inherited susceptibility. Project 3 will seek to identify and validate tumor- and blood-based predictive biomarkers of response to systemic immune checkpoint blockade in patients with metastatic urothelial cancer in the context of a randomized, multicenter trial. Project 4 will seek to identify predictive biomarkers of Bacillus Calmette-Guerin (BCG) response and BCG strains with greater activity as a prelude to future clinical trials. Each of these projects will be supported by the Biospecimen Repository and the Biostatistics and Bioinformatics Core, which will assist with the preparation and analysis of human tissues and genomic, immune, and clinical data, and an Administrative Core will ensure project integration. Finally, developmental research projects and career mentorship are fully integrated into the SPORE to ensure that a future generation of researchers is prepared to further advance our long-term objectives of enhancing therapy, reducing the morbidity of treatments, and ultimately eliminating this disease as a cause of premature death.