Genomic and Microenvironmental Determinants, Temporal Dynamics, and Treatment Efficacy of Radiation-Based Combination Therapies

基因组和微环境决定因素、时间动态以及基于放射的联合疗法的治疗效果

• 批准号: 10704661
• 负责人: Timothy An-thy Chan
• 金额: $ 147.36万
• 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/10704661
• 关键词: Antibody-drug conjugates; Automobile Driving; Biography; Biological Markers; Biological Products; Bladder; Breast Cancer Patient; Cancer Patient; Chemotherapy and/or radiation; Cisplatin; Clinic; Clinical; Combined Modality Therapy; DNA Damage; Data; Disease; Event; Foundations; Gene Expression; Genetic; Genetic Transcription; Genomics; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Immune; Immune checkpoint inhibitor; Immune system; Immunologic Factors; Immunologics; Immunotherapy; International; Malignant neoplasm of urinary bladder; Modality; Molecular; Mutation; Oncology; Outcome; Pathogenesis; Patients; Radiation; Radiation Tolerance; Radiation therapy; Radiobiology; Research; Research Personnel; Resistance; Robin bird; Roentgen Rays; Testing; Therapeutic; Treatment Efficacy; Work; antitumor effect; cancer therapy; cancer type; checkpoint therapy; chemotherapy; immune checkpoint blockade; improved; improved outcome; innovation; insight; multidisciplinary; multimodality; next generation; preservation; programs; radiation effect; radiation resistance; radiation response; radiomics; response; standard of care; treatment strategy; tumor

PROJECT SUMMARY Overall Section Our ROBIN center focuses on elucidating the genomic and microenvironmental determinants, and temporal dynamics underlying efficacy of radiation-based combination therapies. Radiotherapy (RT), alone or in combination with other treatments, is used to treat about two-thirds of all cancer patients. Despite the widespread use of radiation therapy in oncology, our understanding of the mechanisms driving response and resistance remains poor. Our long-term goal is to understand the mechanisms that underlie efficacy and resistance of radiation-based therapies. New efforts to improve treatment for many cancer types now focus on using combination therapies in which radiation is used with systemic agents, highlighting the urgent need to understand the drivers of efficacy. Among the most promising new biologics being studied for use with radiation are antibody-drug conjugates (ADC) and immune checkpoint inhibitors (ICI). We will use an innovative molecular characterization trial testing radiation plus ADC in bladder cancer and radiation plus ICI in head and neck cancer to characterize the mechanistic drivers underlying these next generation RT-based combinations. The central hypothesis of this U54 application is that specific genetic and immunologic mechanisms underlie sensitivity and resistance to radiation-based combination therapies. We will address these questions through 3 specific aims. In Aim 1, we will work to understand the molecular mechanisms that underlie efficacy of treatment with radiation plus ADC. Here, our working hypothesis is that specific genetic and immunologic events underlie response to RT plus sacituzumab govitecan (SG) treatment. We will leverage our molecular characterization trial (Part A) investigating the use of RT and sacituzumab for bladder preservation therapy. We will determine the differential molecular effects with standard-of-care RT + cisplatin versus RT + SG. In Aim 2, we will improve identification of patients who are sensitive or resistant to RT-based therapies based on new insights into transcriptional dynamics and temporal reprogramming during treatment with radiation-based therapies. Here, we will leverage our molecular characterization trial treating head and neck squamous cell carcinoma (HNSCC) or bladder cancer patients with RT + chemotherapy versus RT + SG or ICI. We will build on recent experimental and clinical breakthroughs led by our research groups, which have identified highly refined gene expression programs associated with RT sensitivity and delta radiomics. In Aim 3, we will identify the differential mechanisms underlying the anti-tumor activities of RT + cisplatin versus RT + immune checkpoint blockade. Here, using our head and neck trial (Part B), we will uncover the unique genetic and immunologic factors that govern response to RT when combined with these two classes of agents. We will elucidate the differential molecular effects of the two approaches, immune reprogramming, and mechanisms of acquired resistance. Our studies will help build a foundation to optimize multimodal, radiation- based definitive treatment strategies.

项目总结