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

项目总结 研究项目1 肌肉浸润性膀胱癌(MIBC)患者保留器官的标准护理包括 同步放化疗(RT)。然而，即使在接受了目前的治疗方法(手术或 化疗)，膀胱保存率和总存活率仍然较低，约为50-60%。这个 膀胱癌的分子发病机制和放化疗耐药机制尚不清楚 明白了。我们的长期目标是了解膀胱癌的疗效和耐药机制。 放射治疗加舒舒珠单抗或顺铂，并利用这一信息开发更好的治疗方式 适用于膀胱癌患者。可能是最有前景的免疫调节生物制品之一，用于放射治疗 是抗体-药物结合物(ADC)。Sacituzumab gov.itecan(SG)是一种抗体药物结合物， 将抗TROP2抗体与伊立替康的活性代谢物结合。ADC通过诱导肿瘤细胞发挥作用 损害以及免疫激活。这一应用的中心假设是特定的基因和 免疫决定因素是SG放射联合治疗的敏感性和抵抗力的基础 ADC与顺铂在MIBC患者中的对比研究我们的假设是建立在强大的初步数据基础上的 来自我们组的。我们计划用三个具体目标来实现我们的目标。在目标1中，我们将阐明 基因和微环境机制驱动对联合saituzumab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 标准护理放疗+顺铂与放疗+ADC的疗效比较。我们还将利用 单细胞测序揭示MIBC患者肿瘤生态系统中与治疗相关的变化 接近。在目标2中，我们将描述肿瘤克隆动力学、免疫谱系编辑和成像 使用saituzumab加放射治疗后的变化。我们推测，ADC治疗可能会导致 塑造肿瘤克隆变体和免疫微环境，并与改进的 对放射治疗的反应。我们将揭示辐射+顺铂与辐射+的适应性变化 使用全面的基因组、转录和免疫学分析的ADC。我们将整合时间上的 肿瘤克隆动力学和免疫谱系编辑与肿瘤基因组学和成像。在《目标3》中，我们将 研究辐射加顺铂与辐射加沙替珠单抗的获得性耐药机制。 我们将揭示这两种治疗方法的不同效果，系统地表征 驱动程序突变的出现，肿瘤克隆成分的变化，免疫重新编程，以及识别 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.