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: 10873384
• 负责人: David Guy Kirsch
• 金额: $ 90.22万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-16 至 2029-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10873384
• 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; 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; 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; randomized, clinical trials; 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.

项目摘要/摘要 放射治疗可用于治疗所有癌症患者的一半。对于某些患者， 放射治疗可以实现局部肿瘤控制和治愈。对于其他患者，放射治疗 姑息症状并减轻痛苦。但是，放射治疗也会引起急性毒性 以及后期影响，降低了生活质量。我们的研究计划的目的是扩大 通过解剖正常组织辐射损伤的机制和 肿瘤对放射疗法的反应。由于我是肉瘤辐射肿瘤学家，我的研究小组不仅 研究肉瘤对放射疗法的反应，还研究肉瘤的发育和转移。期间 先前的资金期，我们调整了CRISPR/CAS9技术来开发新颖的基因工程 肉瘤的小鼠模型，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剂，这是新癌症的潜在靶标 疗法。我们还使用新的鼠标和体外模型来发现一种新的机制 粘液类脂肪肉瘤的精致放射敏感性：DNA破坏诱导的prion样磷酸化 Fus-Chop融合蛋白中的结构域破坏了与染色质重塑配合物的相互作用 肿瘤维持所需的是。我们用新型肉瘤模型启动了新项目 高肿瘤突变负担揭示了肿瘤内部和免疫介导的机制 对放射疗法和免疫疗法的反应和抵抗力。我们的发现为 肉瘤患者的随机临床试验测试具有免疫检查点抑制的放射治疗。 我们还使用基因工程小鼠来发现调节急性毒性和的机制 辐射的后期作用，例如辐射癌变。我们提出的研究将基于 我们最近工作的成功。我们将使用创新的模型系统和复杂的方法 在三个广泛的领域中发现： 1。肉瘤对放射治疗的反应 2。肉瘤对放射线和免疫疗法的反应和抗性 3。辐射因正常组织损伤 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，但也将为未来的临床试验设计，旨在扩大 放射疗法的治疗比率，以改善肉瘤和其他患者的结果 癌症。

项目成果

A precision 3D conformal treatment technique in rats: Application to whole-brain radiotherapy with hippocampal avoidance.

• DOI: 10.1002/mp.12533
• 发表时间: 2017-11
• 期刊: Medical physics
• 影响因子: 3.8
• 作者: Yoon SW;Cramer CK;Miles DA;Reinsvold MH;Joo KM;Kirsch DG;Oldham M
• 通讯作者: Oldham M

Generation and comparison of CRISPR-Cas9 and Cre-mediated genetically engineered mouse models of sarcoma.

• DOI: 10.1038/ncomms15999
• 发表时间: 2017-07-10
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Huang J;Chen M;Whitley MJ;Kuo HC;Xu ES;Walens A;Mowery YM;Van Mater D;Eward WC;Cardona DM;Luo L;Ma Y;Lopez OM;Nelson CE;Robinson-Hamm JN;Reddy A;Dave SS;Gersbach CA;Dodd RD;Kirsch DG
• 通讯作者: Kirsch DG

Tumor-propagating side population cells are a dynamic subpopulation in undifferentiated pleomorphic sarcoma.

• DOI: 10.1172/jci.insight.148768
• 发表时间: 2021-11-22
• 期刊: JCI insight
• 影响因子: 8
• 作者: Tang YJ;Puviindran V;Xiang Y;Yahara Y;Zhang H;Nadesan P;Diao Y;Kirsch DG;Alman BA
• 通讯作者: Alman BA

Dual-energy micro-CT functional imaging of primary lung cancer in mice using gold and iodine nanoparticle contrast agents: a validation study.

• DOI: 10.1371/journal.pone.0088129
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ashton JR;Clark DP;Moding EJ;Ghaghada K;Kirsch DG;West JL;Badea CT
• 通讯作者: Badea CT

The Role of Radiotherapy for Chordoma Patients Managed With Surgery: Analysis of the National Cancer Database.

• DOI: 10.1097/brs.0000000000003406
• 发表时间: 2020-06-15
• 期刊: Spine
• 影响因子: 3
• 作者: Dial BL;Kerr DL;Lazarides AL;Catanzano AA;Green CL;Risoli T Jr;Blazer DG;Goodwin RC;Brigman BE;Eward WC;Larrier NA;Kirsch DG;Mendoza-Lattes SA
• 通讯作者: Mendoza-Lattes SA