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: 10586034
• 负责人: Fang Li
• 金额: $ 51.6万
• 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/10586034
• 关键词: ATM deficient; ATM gene; Abscopal effect; Antibodies; Biogenesis; Biological; Cancer Patient; Cells; 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; 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; anti-PD1 therapy; anticancer research; ataxia telangiectasia mutated protein; cancer cell; cancer immunotherapy; cancer therapy; checkpoint therapy; clinical trial readiness; experimental study; immune cell infiltrate; immune checkpoint blockade; improved; in vivo; inhibitor; insight; knockout gene; malignant breast neoplasm; neoplastic cell; novel; novel strategies; pancreatic cancer model; response; restraint; small molecule inhibitor; synergism; 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.

项目概要 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。 尽管分子机制涉及癌症患者对药物的不同反应 免疫检查点治疗仍不清楚，普遍的共识是肿瘤具有高 突变负担或具有炎症表型的肿瘤更有可能对免疫产生反应 由于存在大量抗肿瘤 T 细胞，因此需要进行检查点治疗。由此可见 改善免疫检查点治疗的主要挑战是操纵肿瘤 微环境因此从抗肿瘤 T 细胞很少的“冷”环境转变为具有抗肿瘤 T 细胞的“热”环境 许多抗肿瘤T细胞。因此，可以增加炎症的方法和药剂 肿瘤微环境的“热度”备受追捧。另一方面，放射治疗， 它已被用于治疗局部肿瘤，最近被证明可以激活免疫 信号通路。这些发现提出了一种诱人的可能性，即 通过操纵肿瘤免疫微环境可以增强放射治疗。 在这个项目中，我们将检验 ATM 抑制是一种有效方法的假设 通过下调线粒体生物发生来激活 cGAS/STING 通路，以实现 ICB 治疗 并增强放射治疗的远隔效应。 我们首先将进行实验以确定 ATM 抑制是否可以显着增强 使用 CRISPR 介导的 ATM 基因敲除进行 ICB 治疗（目标 1）。我们也将尝试 定义涉及 ATM 抑制的下游分子机制和因素 - 介导的 ICB 治疗增强（目标 2）。此外，我们将评估小分子是否 ATM 抑制剂可以增强 ICB 治疗和全身（即远隔）效应 同基因小鼠肿瘤模型中的放射治疗（目标 3）。 项目完成后，我们希望能够深入了解 ATM 在以下领域的作用： 抑制细胞先天免疫的激活。这种理解可能有助于快速 开发增强 ICB 治疗和放射治疗的新方法。