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

项目摘要 整个截面 我们的罗宾中心专注于阐明基因组和微环境决定因素， 基于放射的组合疗法的功效的时间动力学基础。放疗（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使用，我们对驱动反应的机制的理解， 抵抗力仍然很差。我们的长期目标是了解疗效的机制， 对放射治疗的抵抗力。改善许多癌症类型治疗的新努力现在集中在 使用联合疗法，其中放射与全身性药物一起使用，突出了迫切需要 理解功效的驱动因素。在正在研究的最有前途的新生物制剂中， 用于放射治疗的药物是抗体-药物缀合物（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测试膀胱癌中的辐射加ADC以及膀胱癌中的辐射加ICI。 头颈部癌症，以表征这些下一代基于RT的 组合。这种U 54应用的中心假设是，特定的遗传和免疫 这些机制是对基于辐射的组合疗法的敏感性和抗性的基础。我们将解决 这些问题通过三个具体目标。在目标1中，我们将致力于了解 是放疗加ADC治疗有效性的基础。在这里，我们的工作假设是，特定的遗传和 免疫事件是对RT加萨希珠单抗戈维替康（SG）治疗的应答的基础。我们将利用我们 研究RT和sacituzumab用于膀胱保存的分子表征试验（A部分） 疗法我们将确定标准治疗RT +顺铂与RT +顺铂的差异分子效应。 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 基于对治疗过程中转录动力学和时间重编程的新见解， 放射治疗。在这里，我们将利用我们的分子表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我们将建立在我们的研究小组最近领导的实验和临床突破的基础上， 鉴定了与RT敏感性和Δ放射组学相关的高度精炼的基因表达程序。在Aim中 3，我们将确定RT +顺铂与RT +顺铂的抗肿瘤活性的差异机制。 免疫检查点阻断。在这里，使用我们的头颈部试验（B部分），我们将揭示独特的基因 以及当与这两类药剂组合时控制对RT的应答的免疫因子。我们 将阐明这两种方法的不同分子效应，免疫重编程， 获得性抗性的机制。我们的研究将有助于建立一个基础，以优化多式联运，辐射- 基于明确的治疗策略。

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.