Improving the therapeutic efficacy of chemoradiation by targeting the DNA damage response

通过靶向 DNA 损伤反应提高放化疗的治疗效果

基本信息

批准号：
10044069
负责人：
Leslie Anne Parsels
金额：
$ 14.38万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-12 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10044069
关键词：
Antimetabolites Award Biological Markers Biopsy Cancer Biology Cell Cycle Checkpoint Clinic Clinical Trials Clinical Trials Design Collaborations Comb animal structure Confocal Microscopy Conformal Radiotherapy DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Inhibition DNA Repair Pathway Data Defect Development Fiber Flow Cytometry Funding Future Genetic Goals Immunohistochemistry Innovative Therapy Laboratories Locally Advanced Malignant Neoplasm Malignant Neoplasms Methodology Michigan Modeling Normal Cell Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Physicians Primary Lesion Protein Analysis Radiation Radiation Induced DNA Damage Radiation therapy Radiobiology Research Scientist Site Skin Sorting - Cell Movement Training Translating Translations Treatment Efficacy Universities X-Ray Computed Tomography Xenograft procedure base bioluminescence imaging cellular targeting chemoradiation image guided immune checkpoint blockade improved inhibitor/antagonist neoplasm immunotherapy neoplastic cell pre-clinical preclinical development prevent protein activation radiation response replication stress response single cell proteins standard of care targeted biomarker therapeutic target treatment response tumor

项目摘要

ABSTRACT There is an urgent need to improve the efficacy of chemoradiation therapy for patients with locally advanced cancers. Since unrepaired DNA double strand breaks (DSB) are the primary lesions responsible for the therapeutic efficacy of chemoradiation therapy, targeting cellular DNA damage response (DDR) pathways to prevent efficient DNA repair is a promising approach to enhance the efficacy of chemoradiation therapy. Defects in the DDR occur in a majority of cancers, suggesting targeted inhibition of the DDR would also provide an opportunity to selectively enhance sensitivity to chemoradiation in tumor compared to normal cells. Furthermore, our recent data demonstrate that DDR inhibition synergizes with radiation to confer sensitivity to immune checkpoint blockade (ICB) therapy. My training in cancer and radiation biology and pharmacology as well as my collaborations with Dr. Ted Lawrence and other physician-scientists at the University of Michigan make me uniquely well-qualified to develop innovative therapies combining DDR inhibitors, ICB and radiation. My effort is currently funded by U01 CA2166449 entitled, “Sensitization to chemoradiation by therapeutic targeting of the DNA damage response.” The overall goals of this project are to 1) evaluate DDR inhibitory drugs for their ability to modulate the cellular response to radiation-induced DNA damage and sensitize tumor cells to standard of care chemoradiation therapy 2) develop viable biomarkers for target engagement and/or therapeutic response and 3) translate our preclinical findings to rationally-designed clinical trials. As my research focus has evolved from antimetabolite-induced cell cycle checkpoints to targeted inhibition of DNA repair pathways, exploitation of replication stress and most recently anti-tumor immunotherapy, I have mastered a wide variety of state-of-the- art methodologies that have allowed me to critically assess the key determinants of therapeutic response including: flow cytometry and sorting for single cell protein analysis; confocal microscopy to track protein activation and localization at sites of DNA DSBs; immunohistochemistry to verify pharmacodynamic target inhibition in skin biopsies; DNA fiber combing to assess replication stress; and patient-derived xenograft based models of tumor response including their treatment with CT and bioluminescence image-guided conformal radiation. Furthermore, I am adept at developing complementary genetic and pharmacological models to critically assess the relative contributions of modulation of the DDR to therapeutic response and translating those results to the development of viable biomarkers for both target engagement and therapeutic efficacy as evidenced by our recently completed clinical trial. This award will enable me to continue the preclinical development of DDR inhibitors and ICB in combination with radiation therapy that will inform future clinic trials for patients with locally advanced cancers.

抽象的迫切需要提高局部晚期患者放化疗的疗效由于未修复的 DNA 双链断裂 (DSB) 是导致癌症的主要病变。放化疗的治疗效果，针对细胞 DNA 损伤反应 (DDR) 途径防止有效的DNA修复是增强放化疗缺陷疗效的一种有前景的方法。 DDR 发生在大多数癌症中，表明靶向抑制 DDR 也将提供一种与正常细胞相比，有机会选择性增强肿瘤对放化疗的敏感性。我们最近的数据表明，DDR 抑制与辐射协同作用，赋予免疫敏感性我在癌症和放射生物学和药理学方面的培训以及我的检查点封锁（ICB）疗法。与密歇根大学特德·劳伦斯博士和其他医学科学家的合作使我我有资格开发结合 DDR 抑制剂、ICB 和放射的创新疗法。目前由 U01 CA2166449 资助，题为“通过治疗靶向治疗对放化疗的敏感性” DNA 损伤反应。”该项目的总体目标是 1) 评估 DDR 抑制药物的能力调节细胞对辐射诱导的 DNA 损伤的反应并使肿瘤细胞对标准敏感护理放化疗 2) 开发用于目标参与和/或治疗反应的可行生物标志物 3）随着我的研究重点的发展，将我们的临床前研究结果转化为合理设计的临床试验。从抗代谢物诱导的细胞周期检查点到 DNA 修复途径的靶向抑制，复制压力和最近的抗肿瘤免疫疗法，我已经掌握了多种最新技术艺术方法论使我能够批判性地评估治疗反应的关键决定因素包括：用于单细胞蛋白质分析的流式细胞术和分选，以追踪蛋白质； DNA DSB 位点的激活和定位；免疫组织化学以验证药效学靶标皮肤活检中的抑制；DNA纤维梳理以评估复制压力和基于患者的异种移植物；肿瘤反应模型，包括 CT 和生物发光图像引导适形治疗此外，我擅长开发互补的遗传和药理学模型来批判性地进行研究。评估 DDR 调节对治疗反应的相对贡献并转化这些结果开发用于目标参与和治疗效果的可行生物标志物，如以下所证明我们最近完成的临床试验将使我能够继续 DDR 的临床前开发。抑制剂和 ICB 与放射治疗相结合，将为未来针对局部患有癌症的患者进行临床试验提供信息晚期癌症。