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: 10526303
• 负责人: Timothy An-thy Chan
• 金额: $ 19.32万
• 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/10526303
• 关键词: ATM Gene Mutation; Antibodies; Antibody-drug conjugates; Bladder; Blood; Cancer Patient; Cells; 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; Molecular Genetics; 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; Tumor-infiltrating immune cells; Urothelium; Variant; antitumor effect; base; cancer cell; cell injury; chemoradiation; chemotherapy; driver mutation; immune activation; immune checkpoint; immunoregulation; improved; improved outcome; irinotecan; molecular imaging; 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 microenvironment; 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.

项目总结