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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要研究项目1 肌浸润性膀胱癌 (MIBC) 患者的器官保留标准护理包括同步化疗加放疗（RT）。然而，即使在接受当前的治疗（手术或放化疗），膀胱保留率和总生存率仍然较低，约为 50-60%。这膀胱癌的分子发病机制和放化疗耐药机制仍不清楚明白了。我们的长期目标是了解膀胱癌的疗效和耐药机制放射加 sacituzumab 或顺铂，并利用这些信息开发更好的治疗方式对于膀胱癌患者。也许是与辐射一起使用的最有前途的免疫调节生物制品之一是抗体药物偶联物（ADC）。 Sacituzumab govitecan (SG) 是一种抗体药物缀合物，将抗 TROP2 抗体与伊立替康的活性代谢物相结合。 ADC 通过诱导肿瘤细胞发挥作用损伤以及免疫激活。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 联合疗法的敏感性和耐药性的基础 MIBC 患者中 ADC 与顺铂的比较。我们的假设是基于强有力的初步数据制定的来自我们组。我们计划通过 3 个具体目标来实现我们的目标。在目标 1 中，我们将阐明驱动 sacituzumab 联合用药疗效和耐药性的遗传和微环境机制膀胱癌的放射治疗。这里的工作假设是不同肿瘤的组合决定因素，例如 DDR 基因的体细胞突变和微环境特征，可能很重要 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 治疗的效果。我们还将利用单细胞测序揭示 MIBC 中肿瘤生态系统与治疗相关的变化方法。在目标 2 中，我们将描述肿瘤克隆动力学、免疫库编辑和成像的特征 sacituzumab 加放疗后发生的变化。我们假设 ADC 治疗可能会导致塑造肿瘤克隆变异和免疫微环境，并与改善相关对放射治疗的反应。我们将揭示放射+顺铂与放射+的适应性变化使用全面的基因组、转录和免疫学分析的 ADC。我们将整合时间肿瘤克隆动力学和肿瘤基因组学和成像的免疫库编辑。在目标 3 中，我们将检查放射加顺铂与放射加 sacituzumab 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，系统地表征驱动突变的出现、肿瘤克隆组成的变化、免疫重编程以及识别获得性耐药的分子和细胞机制。