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: 10875876
• 负责人: Timothy An-thy Chan
• 金额: $ 7.09万
• 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/10875876
• 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.

项目概要 整体剖面 我们的 ROBIN 中心专注于阐明基因组和微环境决定因素，以及 基于放射的联合疗法疗效的时间动态。单独放疗 (RT) 或 与其他治疗相结合，可治疗约三分之二的癌症患者。尽管 放射治疗在肿瘤学中的广泛使用，我们对驱动反应机制的理解以及 抵抗力依然较差。我们的长期目标是了解功效和作用背后的机制 放射治疗的耐药性。改善多种癌症治疗的新努力现在集中于 使用放射与全身药物联合使用的联合疗法，突出表明迫切需要 了解功效的驱动因素。正在研究的最有前途的新型生物制剂之一 放射治疗包括抗体药物偶联物（ADC）和免疫检查点抑制剂（ICI）。我们将使用一个 创新分子表征试验测试放射加 ADC 治疗膀胱癌以及放射加 ICI 治疗膀胱癌 头颈癌来表征这些下一代基于 RT 的潜在机械驱动因素 组合。该 U54 应用的中心假设是特定的遗传和免疫学 对基于放射的联合疗法的敏感性和耐药性的机制。我们将解决 这些问题通过 3 个具体目标来解决。在目标 1 中，我们将努力了解以下分子机制： 放射加 ADC 治疗效果的基础。在这里，我们的工作假设是特定的遗传和 免疫事件是 RT 加 sacituzumab govitecan (SG) 治疗反应的基础。我们将利用我们的 分子表征试验（A 部分）研究 RT 和 sacituzumab 在膀胱保存中的应用 治疗。我们将确定标准治疗 RT + 顺铂与 RT + 的不同分子效应 SG。在目标 2 中，我们将改进对基于 RT 的疗法敏感或耐药的患者的识别 基于对治疗过程中转录动力学和时间重编程的新见解 基于放射的治疗。在这里，我们将利用我们的分子表征试验治疗头颈部 鳞状细胞癌 (HNSCC) 或膀胱癌患者接受 RT + 化疗与 RT + SG 或 ICI。我们将以我们的研究小组领导的最新实验和临床突破为基础，这些突破已经 确定了与 RT 敏感性和 delta 放射组学相关的高度精细的基因表达程序。瞄准 3，我们将确定 RT + 顺铂与 RT + 抗肿瘤活性的差异机制 免疫检查点封锁。在这里，通过我们的头颈试验（B 部分），我们将揭示独特的基因 与这两类药物联合使用时控制放疗反应的免疫因素。我们 将阐明这两种方法的不同分子效应，免疫重编程和 获得性耐药机制。我们的研究将有助于建立优化多模式、辐射的基础 为基础的明确治疗策略。