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

基本信息

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
项目类别：
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

项目摘要

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滞（ICB）治疗最近在癌症治疗方面表现出了巨大的希望。但是，目前只有少数患者可以从免疫检查点疗法中受益。尽管与癌症患者差异反应有关的分子机制免疫检查点疗法尚不清楚，一般共识是突变烧伤或具有炎症表型的肿瘤更有可能对免疫反应检查点治疗由于存在较高数量的抗肿瘤T细胞。它出现了改善免疫检查点疗法的主要挑战是操纵肿瘤微环境使其从几乎没有抗肿瘤T细胞的“冷”变为一个“热”，一个“热” 许多抗肿瘤T细胞。因此，可以增加炎症的方法和药物肿瘤微环境的“热度”紧随其后。另一方面，放疗，已用于治疗局部肿瘤的，最近已显示出激活免疫信号通路。这些发现提出了诱人的可能性可以通过操纵肿瘤免疫微环境来增强放射疗法。在这个项目中，我们将研究以下假设：ATM抑制是一种有效的方法通过下调线粒体生物发生来激活CGA/STING途径以实现ICB治疗并增强放射疗法的潜在影响。我们最初将进行实验，以确定ATM抑制是否可以显着增强 ICB治疗ATM的CRISPR介导的基因敲除（AIM 1）。我们还将尝试定义涉及ATM抑制的下游分子机制和因子 ICB治疗的介导的增强（AIM 2）。另外，我们将评估是否一个小分子 ATM的抑制剂可以增强ICB治疗和全身性（即潜线）影响合成小鼠肿瘤模型中的放射疗法（AIM 3）。该项目完成后，我们希望我们可以对ATM在限制细胞先天免疫的激活。这种理解可能会促进快速开发新的方法来增强ICB治疗和放射疗法。