SPORE in Bladder Cancer

膀胱癌中的孢子

• 批准号: 10226965
• 负责人: Dean F. Bajorin
• 金额: $ 213.85万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-24 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226965
• 关键词: Address; Affect; Attenuated; BCG Live; Bioinformatics; Biological Specimen Banks; Biology; Biometry; Bladder; Bladder Urothelium; Blood; Cancer Biology; Cancer Patient; Caring; Cells; Cessation of life; Clinical; Clinical Data; Clinical Management; Clinical Research; Clinical Trials; Community Clinical Oncology Program; Computational Biology; Cost of Illness; Cystectomy; DNA Damage; Decision Making; Development; Diagnosis; Disease; Ensure; Evolution; Expenditure; FDA approved; Future; Future Generations; Gene Mutation; Genetic Predisposition to Disease; Genomic Instability; Genomics; Genus Mycobacterium; Goals; Heritability; Heterogeneity; Human; Immune; Immune Targeting; Immune checkpoint inhibitor; Immune response; Immunotherapy; Individual; Inherited; Investigation; Investigational Therapies; Laboratory Research; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Medical; Mentorship; Minority; Molecular; Molecular Analysis; Molecular Profiling; Monitor; Morbidity - disease rate; Multicenter Trials; Mutation; Organ; Outcome; Palpable; Pathway interactions; Patients; Pattern; Predisposition; Preparation; Prevalence; Primary Neoplasm; Public Health; Randomized; Recording of previous events; Recurrence; Regimen; Renal pelvis; Research Personnel; Research Project Grants; Resistance; Risk; Selection for Treatments; Site; Specialized Program of Research Excellence; Systemic Therapy; The Cancer Genome Atlas; Therapeutic; Time; Translational Research; Transurethral Resection; Treatment Cost; Tuberculosis; Tumor Tissue; United States; Ureter; Urethra; Urothelium; Variant; advanced disease; anti-PD-L1; base; biomarker validation; cancer genetics; cancer genomics; cancer immunobiology; career; chemotherapy; combinatorial; data integration; design; drug discovery; drug sensitivity; efficacy testing; genomic signature; guided inquiry; human tissue; immune checkpoint blockade; improved; improved outcome; individual patient; insight; molecular pathology; multidisciplinary; muscle invasive bladder cancer; mycobacterial; new therapeutic target; non-muscle invasive bladder cancer; novel; novel marker; patient population; patient subsets; personalized care; predictive marker; predictive signature; premature; pressure; programs; prospective; refractory cancer; research clinical testing; resistance mechanism; response; response biomarker; screening; translational scientist; tumor

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.

项目概要/摘要 肿瘤学界明显感到兴奋，因为我们正处于治疗方法重大进展的风口浪尖。 治疗膀胱（尿路上皮）癌。最近全面定义遗传改变景观的努力 尿路上皮癌并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，血液和肿瘤组织的前瞻性分子分析可以 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性遗传的分子基础 敏感性，利用前瞻性分子特征来指导治疗，并测试疗效 基于免疫疗法的组合方法。 MSK SPORE 在膀胱中的总体转化目标 癌症将 1) 开发对免疫疗法、化疗、 和研究性治疗； 2) 识别导致风险增加的种系遗传改变 尿路上皮癌的发展； 3）确定免疫治疗耐药机制并开发 增强尿路上皮癌患者免疫治疗反应的组合策略。追求 为了实现这些目标，我们组建了一支在临床领域具有互补专业知识的多学科团队 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。翻译的 SPORE 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态 疾病的演变。项目 1 将使用前瞻性分子表征来确定 合作团体试验的背景下，无论是经尿道切除术还是化疗，都不需要 膀胱切除术对 DNA 损伤反应基因改变的患者有疗效，并能识别新的 化疗敏感性的生物标志物。项目 2 将鉴定新种系并对其进行功能表征 赋予遗传易感性增加的变异。项目 3 将寻求识别和验证肿瘤和 患有以下疾病的患者对全身免疫检查点阻断反应的基于血液的预测生物标志物 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) 反应的预测生物标志物和具有较高活性的 BCG 菌株 为未来的临床试验拉开序幕。这些项目中的每一个都将得到生物样本库和 生物统计学和生物信息学核心，将协助人体组织和细胞的制备和分析 基因组、免疫和临床数据以及管理核心将确保项目整合。最后， 发展研究项目和职业指导完全融入 SPORE，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， 降低治疗的发病率，并最终消除这种疾病作为过早死亡的原因。