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 总体科 我们的罗宾中心专注于阐明基因组和微环境决定因素，以及 以放射为基础的综合治疗的潜在疗效的时间动力学。放射治疗(RT)，单独或 与其他治疗方法相结合，用于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应用，我们对驱动反应和 抵抗力仍然很差。我们的长期目标是了解疗效和 基于放射治疗的抵抗力。改善多种癌症治疗的新努力现在集中在 使用联合疗法，其中放射与全身药剂一起使用，强调迫切需要 了解疗效的驱动因素。正在研究中的最有前途的新生物制品之一 辐射是抗体-药物结合物(ADC)和免疫检查点抑制物(ICI)。我们将使用 放射加ADC和放射加ICI在膀胱癌中的创新分子表征试验 头颈部癌症表征了这些基于下一代RT的机制驱动因素 组合。U54应用的中心假设是特定的遗传和免疫学 机制是对以辐射为基础的联合疗法的敏感性和抵抗力的基础。我们将解决 这些问题有三个具体目的。在目标1中，我们将努力了解 放射治疗加ADC治疗的基础疗效。在这里，我们的工作假设是特定的基因和 免疫学事件是RT加Sigituzumab gov.itecan(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saituzumab在膀胱保存中的应用 心理治疗。我们将确定标准护理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的治疗敏感或耐药的患者的识别 基于对转录动力学和在治疗期间的时间重新编程的新见解 基于辐射的疗法。在这里，我们将利用我们的分子特征试验治疗头部和颈部 鳞状细胞癌(HNSCC)或膀胱癌患者接受RT+化疗与RT+SG或 ICI。我们将在我们的研究小组领导的最近的实验和临床突破的基础上再接再厉，这些小组已经 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。在AIM 3，我们将确定RT+顺铂和RT+抗肿瘤活性的不同机制 免疫检查站封锁。在这里，使用我们的头和颈部试验(B部分)，我们将揭示独特的基因 以及免疫因素，当与这两类药物结合时，控制对RT的反应。我们 将阐明这两种方法的不同分子效应，即免疫重新编程和 获得性抗性的机制。我们的研究将有助于为优化多式联运、辐射- 基于明确的治疗策略。