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

• 批准号: 10457345
• 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
• 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/10457345
• 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; base; bioluminescence imaging; cellular targeting; chemoradiation; image guided; immune checkpoint blockade; improved; inhibitor; neoplasm immunotherapy; neoplastic cell; patient derived xenograft model; pre-clinical; preclinical development; prevent; protein activation; radiation response; rational design; replication stress; response; single cell proteins; standard of care; targeted biomarker; therapeutic target; treatment response; tumor

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.

摘要 目前迫切需要提高局部晚期乳腺癌患者放化疗的疗效 癌的由于未修复的DNA双链断裂（DSB）是导致DNA损伤的主要病变， 放化疗的疗效，靶向细胞DNA损伤反应（DDR）途径， 阻止有效的DNA修复是提高放化疗疗效的一种有前途的方法。缺陷 在DDR中发生在大多数癌症中，这表明DDR的靶向抑制也将提供一种治疗方法。 与正常细胞相比，有机会选择性地增强肿瘤对放化疗的敏感性。此外，委员会认为， 我们最近的数据表明，DDR抑制与辐射协同作用，使免疫敏感性， 检查点阻断（ICB）治疗。我在癌症和放射生物学和药理学方面的训练， 与密歇根大学的泰德·劳伦斯博士和其他医学科学家的合作使我 我们是唯一有资格开发DDR抑制剂、ICB和放射相结合的创新疗法的公司。我的努力是 目前由U 01 CA 2166449资助，题为“通过治疗靶向靶向化疗的致敏作用”。 DNA损伤反应。”本项目的总体目标是：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的 2）开发用于靶点接合和/或治疗反应的可行生物标志物 和3）将我们的临床前发现转化为合理设计的临床试验。随着我的研究重点的发展 从抗代谢药诱导的细胞周期检查点到靶向抑制DNA修复途径， 复制压力和最近的抗肿瘤免疫疗法，我已经掌握了各种各样的国家的- 艺术的方法，使我能够批判性地评估治疗反应的关键决定因素 包括：流式细胞术和单细胞蛋白分析分选;共聚焦显微镜跟踪蛋白 DNA DSB位点的活化和定位;免疫组织化学验证药效学靶点 皮肤活检中的抑制; DNA纤维梳理以评估复制应激;以及基于患者来源的异种移植物的 肿瘤反应模型，包括CT和生物发光图像引导适形放射治疗 辐射此外，我擅长开发互补的遗传和药理学模型， 评估DDR调节对治疗反应的相对贡献，并转化这些结果 涉及用于靶点接合和治疗功效的可行生物标志物的开发，如由 我们最近完成的临床试验这个奖项将使我能够继续DDR的临床前开发 抑制剂和ICB联合放射治疗，将为未来的临床试验提供信息， 晚期癌症