Advancing Cancer Therapy through Groundbreaking Research in Radiation Biology

通过放射生物学的突破性研究推进癌症治疗

• 批准号: 10517545
• 负责人: David Guy Kirsch
• 金额: $ 95.06万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-04 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10517545
• 关键词: Advanced Malignant Neoplasm; Area; Biological Models; Biology; CRISPR/Cas technology; Cancer Biology; Cancer Patient; Cell Line; Chimeric Proteins; Chromatin Remodeling Factor; Clinical Trials; DNA Damage; Development; Funding; Future; Genetically Engineered Mouse; Goals; Human; Immune; Immunotherapy; Knowledge; Late Effects; Lead; Maintenance; Malignant Neoplasms; Mediating; Modeling; Mus; Mutation; Myxoid Liposarcoma; Neoplasm Metastasis; Normal tissue morphology; Patient-Focused Outcomes; Patients; Phosphorylation; Quality of life; Radiation; Radiation Injuries; Radiation Oncologist; Radiation Tolerance; Radiation therapy; Radiobiology; Randomized Clinical Trials; Research; Resistance; Sampling; Testing; Therapeutic; Work; acute toxicity; cancer therapy; checkpoint inhibition; design; improved; improved outcome; in vitro Model; innovation; novel; palliating symptoms; prion-like; programs; radiation carcinogenesis; radiation effect; radiation response; reduce symptoms; response; sarcoma; success; tumor; tumor progression

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.

项目总结/摘要 放射治疗用于治疗大约一半的癌症患者。对于一些病人来说， 放射治疗可以达到局部肿瘤控制和治愈。对于其他患者，放射治疗 减轻症状减轻痛苦然而，放射治疗也会引起急性毒性 以及降低生活质量的迟发效应。我们研究计划的目标是扩大 解剖正常组织放射损伤机制，探讨放射治疗的治疗窗 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，也研究肉瘤的发展和转移。期间 在上一个资助期，我们采用了CRISPR/Cas9技术来开发新的基因工程 小鼠肉瘤模型，促进肿瘤进展过程中肉瘤克隆的谱系追踪。 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， 粘液样脂肪肉瘤的高放射敏感性：DNA损伤诱导朊病毒样蛋白磷酸化 FUS-CHOP融合蛋白中的结构域破坏与染色质重塑复合物的相互作用 是维持肿瘤生长所必需的我们用一种新的肉瘤模型启动了新的项目， 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。我们的研究结果提供了一个理由， 在肉瘤患者中进行的随机临床试验，测试放射治疗与免疫检查点抑制。 我们还使用我们的基因工程小鼠来揭示调节急性毒性的机制， 辐射的晚期效应，如辐射致癌作用。我们提议的研究将建立在 我们最近工作的成功。我们将使用创新的模型系统和先进的方法， 在三大领域有所发现： 1.肉瘤对放射治疗的反应 2.肉瘤对放射和免疫治疗的反应和抵抗 3.放射性正常组织损伤 从拟议的研究中获得的知识不仅会加深我们对辐射的理解 和肉瘤生物学，但也将告知未来临床试验的设计，旨在扩大 放射治疗的治疗比，以改善肉瘤和其他患者的预后 癌的