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

摘要 迫切需要提高局部晚期肺癌患者的放化疗疗效 癌症。由于未修复的DNA双链断裂(DSB)是导致 靶向细胞DNA损伤反应(DDR)通路的放化疗的疗效 防止有效的DNA修复是提高放化疗疗效的有效途径。缺陷 在大多数癌症中发生的DDR，表明靶向抑制DDR也将提供一种 与正常细胞相比，有选择地提高肿瘤对化疗的敏感性的机会。此外， 我们最近的数据表明，DDR抑制与辐射协同作用，增加了对免疫的敏感性 检查点封锁(ICB)疗法。我在癌症、放射生物学和药理学方面的训练，以及我的 与密歇根大学的特德·劳伦斯博士和其他内科科学家的合作让我 独一无二地具备开发DDR抑制剂、ICB和放射治疗相结合的创新疗法的资格。我的努力是 目前由U01 CA2166449资助，标题为“通过治疗靶向进行化疗放射增敏” 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的 CARE放化疗2)为靶点参与和/或治疗反应开发可行的生物标记物 3)将我们的临床前研究成果转化为合理设计的临床试验。随着我的研究重点的演变 从抗代谢诱导的细胞周期检查点到靶向抑制DNA修复途径，开发 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状态- ART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；用于跟踪蛋白质的共聚焦显微镜 DNADSB的激活和定位；免疫组织化学验证药效学靶点 皮肤活组织检查中的抑制；DNA纤维梳理以评估复制压力；以及基于患者来源的异种移植 肿瘤反应模型，包括CT和生物发光成像引导的适形放射治疗 辐射。此外，我擅长开发互补的遗传和药理学模型，以关键 评估DDR调节对治疗反应的相对贡献，并将这些结果转化为 对于靶点结合和治疗效果的可行生物标志物的开发，如以下所证明的 我们最近完成的临床试验。这一奖项将使我能够继续DDR的临床前开发 抑制剂和ICB与放射治疗相结合，将为当地患者未来的临床试验提供信息 晚期癌症。

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.