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.

项目摘要 整个部分 我们的罗宾中心重点是阐明基因组和微环境决定因素，以及 基于辐射组合疗法的时间动力学的基础动力学。放疗（RT），单独或 结合其他治疗方法，用于治疗所有癌症患者中约三分之二。尽管有 广泛使用放射疗法在肿瘤学中，我们对推动反应的机制的理解和 抵抗仍然很差。我们的长期目标是了解效力和效力的机制 基于辐射的疗法的抗性。现在，为改善许多癌症类型的治疗的新努力现在关注 使用与全身剂一起使用辐射的组合疗法，强调迫切需要 了解功效的驱动力。在研究中最有希望的新生物制剂中 辐射是抗体 - 药物结合物（ADC）和免疫检查点抑制剂（ICI）。我们将使用 创新的分子表征试验试验测试辐射以及膀胱癌和辐射中的ADC以及ICI 头颈癌以表征这些基于RT的下一代机械驱动因素 组合。该U54应用的中心假设是特定的遗传和免疫学 机制是敏感性和对基于辐射的组合疗法的抗性的基础。我们将解决 这些问题通过3个特定目的。在AIM 1中，我们将努力了解分子机制 辐射和ADC治疗的疗效基础。在这里，我们的工作假设是特定的遗传和 免疫事件是对RT加Sacituzumab Govitecan（SG）治疗的反应的基础。我们将利用我们的 分子表征试验（A部分）研究了使用RT和Sacituzumab用于膀胱保存的方法 治疗。我们将确定具有标准RT +顺铂与RT +的差异分子效应 SG。在AIM 2中，我们将提高对基于RT疗法的敏感或抗性患者的识别 基于对转录动力学和时间重编程的新见解 基于辐射的疗法。在这里，我们将利用分子表征试验治疗头颈 鳞状细胞癌（HNSCC）或RT +化学疗法的膀胱癌患者与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 确定了与RT敏感性和三角洲放射线学相关的高度精制基因表达程序。目标 3，我们将确定RT +顺铂与RT +的抗肿瘤活性的差异机制 免疫检查点封锁。在这里，使用我们的头颈试验（B部分），我们将发现独特的遗传 与这两类药物结合使用时，控制RT反应的免疫学因素。我们 将阐明两种方法的差异分子效应，免疫重编程，并 获得的抗性机制。我们的研究将有助于建立基础，以优化多模式，辐射 - 基于确定的治疗策略。