Project 1 Genetic and Immunologic Mechanisms Underlying Combination Sacituzumab plus Radiation Therapy for Bladder Cancer

项目 1 Sacituzumab 联合放射治疗膀胱癌的遗传和免疫机制

• 批准号: 10704713
• 负责人: Timothy An-thy Chan
• 金额: $ 16.46万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-14 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704713
• 关键词: ATM Gene Mutation; Antibodies; Antibody-drug conjugates; Biological Response Modifiers; Bladder; Blood; Cancer Patient; Cells; Cessation of life; Cisplatin; Clinical; Clinical Trials; Clonality; Combined Modality Therapy; DNA Damage; Data; Diagnosis; Dissection; Ecosystem; Evolution; Genes; Genetic; Genetic Transcription; Genomics; Goals; Image; Immune; Immune checkpoint inhibitor; Immunologics; Kinetics; Malignant neoplasm of urinary bladder; Modality; Molecular; Mutation; Operative Surgical Procedures; Organ; Outcome; Pathogenesis; Patient Care; Patients; Phenotype; Population; Prospective Studies; Radiation; Radiation therapy; Research Project Grants; Research Project Summaries; Resistance; Sampling; Somatic Mutation; TP53 gene; Testing; Therapeutic; Transurethral Resection; Treatment Efficacy; Urothelium; Variant; antitumor effect; cancer cell; cell injury; checkpoint therapy; chemoradiation; chemotherapy; driver mutation; immune activation; immune cell infiltrate; improved; improved outcome; irinotecan; muscle invasive bladder cancer; neoplastic cell; next generation; overexpression; preservation; prospective; radiation effect; radiation response; resistance mechanism; response; single cell sequencing; standard of care; treatment effect; tumor; tumor-immune system interactions

PROJECT SUMMARY Research Project 1 An organ sparing standard-of-care for patients with muscle invasive bladder cancer (MIBC) involves concurrent chemotherapy plus radiation (RT). However, even after receiving current therapies (surgery or chemoradiation), bladder preservation and overall survival remains low, at approximately 50-60%. The molecular pathogenesis of bladder cancer and the mechanisms of resistance to chemoradiation remain poorly understood. Our long-term goal is to understand the mechanisms of efficacy and resistance of bladder cancer to radiation plus sacituzumab or cisplatin and to use this information to develop better therapeutic modalities for bladder cancer patients. Perhaps one of most promising immunomodulatory biologicals used with radiation is the antibody-drug conjugates (ADC). Sacituzumab govitecan (SG) is an antibody drug conjugate that combines the anti-TROP2 antibody with an active metabolite of irinotecan. ADCs act by inducing tumor cell damage as well as immune activation. The central hypothesis of this application is that specific genetic and immune determinants underlie sensitivity and resistance to radiation-based combination therapies with SG ADC versus cisplatin in MIBC patients. Our hypothesis has been formulated based on strong preliminary data from our group. We plan to accomplish our objectives with 3 specific aims. In Aim 1, we will elucidate the genetic and microenvironmental mechanisms that drive efficacy and resistance to combined sacituzumab plus radiation therapy in bladder cancer. The working hypothesis here is that combinations of distinct tumor determinants, such as somatic mutations in DDR genes, and microenvironmental features, may be important for the anti-tumor effects of RT+SG. We will systematically elucidate the molecular, genetic, and immunologic effects of treatment with standard-of-care radiation + cisplatin versus radiation + ADC. We will also utilize single cell sequencing to reveal treatment-related changes in the tumor ecosystem in MIBC undergoing each approach. In Aim 2, we will characterize tumor clonal dynamics, immune repertoire editing, and imaging changes following treatment with sacituzumab plus radiation. We postulate that ADC therapy may induce sculpting of both the tumor clonal variants and the immune microenvironment and associate with an improved response to radiation treatment. We will reveal adaptive changes to radiation + cisplatin versus radiation + ADC using comprehensive genomic, transcriptional, and immunologic profiling. We will integrate the temporal kinetics of tumor clonality and immune repertoire editing with tumor genomics and imaging. In Aim 3, we will examine the mechanisms of acquired resistance to radiation plus cisplatin versus radiation plus sacituzumab. We will uncover the differential effects of these two treatment approaches, systematically characterize emergence of driver mutations, changes in the tumor clonal composition, immune reprogramming, and identify molecular and cellular mechanisms of acquired resistance.

项目摘要 研究项目1 针对肌肉浸润性膀胱癌（MIBC）患者的器官支撑标准涉及 并发化疗加辐射（RT）。但是，即使接受当前疗法（手术或 化学放疗），膀胱保存和整体生存率保持较低，约为50-60％。这 膀胱癌的分子发病机理和对化学辐射的抗性机制仍然很差 理解。我们的长期目标是了解膀胱癌功效和抗性的机制 辐射加上sacituzumab或顺铂，并使用这些信息来发展更好的治疗方式 对于膀胱癌患者。也许是用于辐射的最有前途的免疫调节生物学之一 是抗体 - 药物缀合物（ADC）。 sacituzumab govitecan（SG）是一种抗体药物结合物 将抗Trop2抗体与伊立替康活性代谢产物结合在一起。 ADC通过诱导肿瘤细胞来起作用 损害以及免疫激活。该应用的中心假设是特定的遗传和 免疫决定因素是敏感性和对基于辐射的组合疗法的抗性的基础 MIBC患者的ADC与顺铂。我们的假设是根据强大的初步数据提出的 来自我们的小组。我们计划以3个特定目标来实现我们的目标。在AIM 1中，我们将阐明 遗传和微环境机制，这些机制促进了疗效和抗性sacituzumab Plus的能力 膀胱癌的放射治疗。这里的工作假设是不同肿瘤的组合 决定因素，例如DDR基因中的体细胞突变和微环境特征，可能很重要 用于RT+SG的抗肿瘤作用。我们将系统地阐明分子，遗传和免疫学 使用标准辐射 +顺铂与辐射 + ADC处理的影响。我们还将利用 单细胞测序以揭示MIBC中肿瘤生态系统中与治疗相关的变化 方法。在AIM 2中，我们将表征肿瘤克隆动力学，免疫曲目编辑和成像 用sacituzumab加辐射治疗后的变化。我们假设ADC治疗可能诱发 塑料肿瘤克隆变体和免疫微环境，并与改善 对辐射处理的反应。我们将揭示对辐射 +顺铂与辐射 +的自适应变化 使用综合基因组，转录和免疫学分析的ADC。我们将整合时间 肿瘤克隆性和免疫曲目编辑的动力学，肿瘤基因组学和成像。在AIM 3中，我们将 检查获得辐射的抗性的机制，以及顺铂与辐射以及sacituzumab的机制。 我们将发现这两种治疗方法的差异效应，从系统地表征 驱动器突变的出现，肿瘤克隆组成的变化，免疫重编程并识别 获得抗性的分子和细胞机制。