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

项目摘要 研究项目1 肌肉浸润性膀胱癌（MIBC）患者的器官保留标准治疗包括 同步化疗加放疗。然而，即使在接受目前的治疗（手术或 放化疗）、膀胱保存和总存活率仍然很低，约为50- 60%。的 膀胱癌的分子发病机制和放化疗抵抗机制仍不清楚 明白我们的长期目标是了解膀胱癌的疗效和耐药机制 放疗加sacituzumab或顺铂，并利用这些信息开发更好的治疗方式 治疗膀胱癌的方法也许是最有前途的免疫调节生物制剂之一， 是抗体-药物缀合物（ADC）。Sacituzumab govitecan（SG）是抗体药物缀合物， 将抗TR 0 P2抗体与伊立替康的活性代谢物组合。ADC通过诱导肿瘤细胞 伤害和免疫激活。本申请的中心假设是特定的遗传和 免疫决定因素是对基于放射的SG联合治疗的敏感性和抵抗性的基础 MIBC患者中的ADC与顺铂。我们的假设是根据强有力的初步数据提出的 从我们组。我们计划通过三个具体目标来实现我们的目标。在目标1中，我们将阐明 遗传和微环境机制驱动联合sacituzumab plus的疗效和耐药性 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，如DDR基因的体细胞突变和微环境特征，可能是重要的 RT+SG的抗肿瘤作用。我们将系统地阐明分子，遗传和免疫学 标准放疗+顺铂与放疗+ ADC治疗的效果。我们还将利用 单细胞测序，揭示接受每次治疗的MIBC中肿瘤生态系统的治疗相关变化 approach.在目标2中，我们将描述肿瘤克隆动力学，免疫库编辑和成像 用sacituzumab加放射治疗后的变化。我们推测ADC治疗可能诱导 肿瘤克隆变体和免疫微环境的塑造，并与改善的 对放射治疗的反应。我们将揭示放射+顺铂与放射+顺铂的适应性变化， ADC使用全面的基因组，转录和免疫分析。我们将整合时间 肿瘤克隆性和免疫库编辑与肿瘤基因组学和成像的动力学。在目标3中，我们 检查对放射加顺铂与放射加sacituzumab的获得性耐药性的机制。 我们将揭示这两种治疗方法的不同效果，系统地描述 驱动突变的出现，肿瘤克隆组成的变化，免疫重编程， 获得性抗性的分子和细胞机制。

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.