Targeting ATM to boost systemic effects of radiotherapy and immunotherapy

靶向 ATM 以增强放射治疗和免疫治疗的全身效应

• 批准号: 10211705
• 负责人: Chuan-Yuan Li
• 金额: $ 52.66万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-09 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211705
• 关键词: ATM deficient; ATM gene; Abscopal effect; Antibodies; Biogenesis; Biological; Cancer Patient; Cells; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Colon Carcinoma; Communities; Consensus; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA-PKcs; Data; Development; Down-Regulation; Face; Genetic; Genomic approach; Goals; Immune; Immune checkpoint inhibitor; Immune signaling; Immunotherapy; Inflammatory; Interferon Type I; Knock-out; Lead; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Methods; Minority; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Mus; Mutation; Natural Immunity; Outcome; Pathway interactions; Patients; Pharmacologic Substance; Phenotype; Play; Public Health; Radiation Tolerance; Radiation therapy; Role; Signal Pathway; Source; Stimulator of Interferon Genes; T memory cell; T-Lymphocyte; Tumor Immunity; Tumor Suppressor Proteins; Tumor-infiltrating immune cells; anti-PD1 therapy; anticancer research; ataxia telangiectasia mutated protein; base; cancer cell; cancer immunotherapy; cancer radiation therapy; cancer therapy; checkpoint therapy; experimental study; immune checkpoint blockade; improved; in vivo; inhibitor/antagonist; insight; knockout gene; malignant breast neoplasm; neoplastic cell; novel; novel strategies; pancreatic cancer model; response; small molecule inhibitor; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions; tumorigenic

PROJECT SUMMARY Immune checkpoint blockade (ICB) therapy has shown great promise in cancer treatment recently. However, currently only a minority of patients could benefit from immune checkpoint therapy. Although the molecular mechanisms involved in the differential responses of cancer patients to immune checkpoint therapy remain unclear, a general consensus is that tumors with high mutational burden or tumors with inflammatory phenotypes are more likely to respond to immune checkpoint therapy due to the presence of higher numbers of anti-tumor T-cells. Thus it appears that the main challenge to improve immune checkpoint therapy is to manipulate the tumor microenvironment so it changes from a “cold” one with few anti-tumor T cells to a “hot” one with many anti-tumor T cells. As such methods and agents that can increase the inflammatory “hotness” of the tumor microenvironment are highly sought after. On the other hand, radiotherapy, which has been used to treat localized tumors, has been recently shown to activate immune signaling pathways. Those discoveries raise the tantalizing possibility that the efficacy of radiotherapy may be enhanced by manipulating the tumor immune microenvironment. In this project, we will examine the hypothesis that ATM inhibition is an effective approach to activate the cGAS/STING pathway by down-regulating mitochondria biogenesis to enable ICB therapy and boosts abscopal effect of radiotherapy. We will initially conduct experiments to determine if ATM inhibition could significantly enhance ICB therapy by use of CRISPR-mediated gene knockout of ATM (Aim 1). We will also attempt to define the downstream molecular mechanisms and factors that are involved ATM inhibition- mediated enhancement of ICB therapy (Aim 2). In addition, we will evaluate if a small molecule inhibitor of ATM could enhance ICB therapy and the systemic (i.e. abscopal) effects of radiotherapy in syngeneic mouse tumor models (Aim 3). Upon completion of the project, we hope we can gain significant insights into the roles of ATM in restraining activation of cellular innate immunity. Such understanding may facilitate the rapid development of novel approaches to enhance ICB therapy and radiotherapy.

项目摘要 免疫检查点阻断（ICB）疗法最近在癌症治疗中显示出巨大的前景。 然而，目前只有少数患者可以从免疫检查点治疗中受益。 尽管参与癌症患者对化疗的不同反应的分子机制， 免疫检查点治疗仍不清楚，普遍的共识是， 突变负荷或具有炎性表型的肿瘤更可能对免疫应答， 检查点疗法，因为存在更多数量的抗肿瘤T细胞。因此，它似乎 改善免疫检查点疗法的主要挑战是操纵肿瘤 因此，它从具有少量抗肿瘤T细胞的“冷”微环境变为具有抗肿瘤T细胞的“热”微环境。 许多抗肿瘤T细胞因此，可以增加炎性细胞因子的方法和试剂 肿瘤微环境的“热度”备受追捧。另一方面，放射治疗， 用于治疗局部肿瘤，最近已被证明可以激活免疫系统， 信号通路这些发现提出了一种诱人的可能性， 可以通过操纵肿瘤免疫微环境来增强放射治疗。 在这个项目中，我们将检验ATM抑制是一种有效的方法的假设， 通过下调线粒体生物发生来激活cGAS/STING途径，以实现ICB治疗 增强放射治疗的远位效果。 我们将首先进行实验，以确定ATM抑制是否可以显着提高 通过使用CRISPR介导的ATM基因敲除的ICB疗法（目的1）。我们还将尝试 定义下游分子机制和涉及ATM抑制的因素- 介导的ICB治疗增强（目的2）。此外，我们还将评估小分子 ATM抑制剂可增强ICB治疗和ATM的全身（即远位）效应。 在同基因小鼠肿瘤模型中进行放射治疗（目的3）。 在项目完成后，我们希望我们可以获得重要的见解ATM的作用， 抑制细胞先天免疫的激活。这样的理解可以促进快速的 开发新的方法来增强ICB治疗和放射治疗。