Advancing Cancer Therapy through Groundbreaking Research in Radiation Biology

项目摘要/摘要 放射治疗被用来治疗大约一半的癌症患者。对于一些病人来说， 放射治疗可以实现局部肿瘤的控制和治愈。对于其他患者，放射治疗 缓解症状，减轻痛苦。然而，放射治疗也会引起急性毒性。 以及降低生活质量的后遗症。我们研究计划的目标是扩大 解剖正常组织放射损伤机制及放射治疗的治疗窗 肿瘤对放疗的反应。由于我是一名肉瘤放射肿瘤学家，我的研究小组不仅 研究肉瘤对放射治疗的反应，以及肉瘤的发展和转移。在.期间 在之前的资助期间，我们采用了CRISPR/Cas9技术来开发新型的基因工程 在肿瘤进展过程中促进肉瘤克隆谱系追踪的小鼠肉瘤模型。 这种方法确定了新的转移调节因子，它们是新癌症的潜在靶点。 治疗。我们还使用了新的小鼠和体外模型来发现一种新的机制 粘液样脂肪肉瘤的精确放射敏感性：DNA损伤诱导的普里子样磷酸化 FUS-CHOP融合蛋白中的结构域干扰与染色质重塑复合体的相互作用 这些都是维持肿瘤所必需的。我们启动了一种新的肉瘤模型的新项目 高肿瘤突变负荷揭示了肿瘤内在和免疫介导的机制 对放射治疗和免疫治疗的反应和抵抗。我们的发现提供了一个理论基础 肉瘤患者接受免疫检查点抑制放射治疗的随机临床试验。 我们还使用我们的基因工程小鼠来揭示调节急性毒性和 辐射的后遗症，如辐射致癌。我们建议的研究将建立在 我们最近的工作取得了成功。我们将用创新的模式体系和尖端的方法来 在三大领域取得新发现： 1.肉瘤对放疗的反应 2.肉瘤对放射治疗和免疫治疗的反应和耐药性 3.辐射对正常组织的损伤 从拟议的研究中获得的知识不仅将加深我们对辐射的理解 和肉瘤生物学，但也将为未来临床试验的设计提供信息，旨在扩大 放射治疗改善肉瘤和其他疾病患者预后的治疗比 癌症。

PROJECT SUMMARY/ABSTRACT Radiation therapy is utilized to treat approximately half of all cancer patients. For some patients, radiation therapy can achieve local tumor control and cure. For other patients, radiation therapy palliates symptoms and alleviates suffering. However, radiation therapy can also cause acute toxicity and late effects that diminish quality of life. The goal of our research program is to widen the therapeutic window of radiation therapy by dissecting mechanisms of normal tissue radiation injury and tumor response to radiotherapy. As I am a sarcoma radiation oncologist, my research group not only studies sarcoma response to radiation therapy, but also sarcoma development and metastasis. During the prior funding period, we adapted CRISPR/Cas9 technology to develop novel genetically engineered mouse models of sarcoma that facilitated lineage tracing of sarcoma clones during tumor progression. This approach identified novel regulators of metastasis, which are potential targets for new cancer therapies. We also used new mouse and in vitro models to discover a novel mechanism for the exquisite radiosensitivity of myxoid liposarcoma: DNA-damage induced phosphorylation of a prion-like domain in the FUS-CHOP fusion protein disrupts interactions with chromatin remodeling complexes that are required for tumor maintenance. We initiated new projects with a novel sarcoma model with high tumor mutation burden that revealed tumor-intrinsic and immune-mediated mechanisms of response and resistance to radiotherapy and immunotherapy. Our findings provided the rationale for a randomized clinical trial in sarcoma patients testing radiation therapy with immune checkpoint inhibition. We also used our genetically engineered mice to uncover mechanisms regulating acute toxicity and late effects of radiation, such as radiation carcinogenesis. Our proposed research will build on the success of our recent work. We will use innovative model systems and sophisticated approaches to make discoveries in three broad areas: 1. Response of sarcomas to radiotherapy 2. Response and resistance of sarcomas to radiation and immunotherapy 3. Normal tissue injury from radiation The knowledge gained from the proposed studies will not only deepen our understanding of radiation and sarcoma biology, but will also inform the design of future clinical trials that aim to widen the therapeutic ratio of radiation therapy to improve the outcome for patients with sarcomas and other cancers.