Anti-tumor efficacy of novel cGAS-STING pathway agonists

新型 cGAS-STING 通路激动剂的抗肿瘤功效

基本信息

批准号：
10286612
负责人：
VICTOR Robert DEFILIPPIS
金额：
$ 19.45万
依托单位：
OREGON HEALTH & SCIENCE 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：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10286612
关键词：
Adverse effects Affect Agonist Alleles Animals Antigen-Presenting Cells Antigens Apoptotic Binding Biological Availability Cancer Model Cancerous Cell Death Cell Maturation Cell secretion Cells Chemosensitization Clinical Clinical Trials Complex Cross-Priming Cyclic GMP Cytoplasm DNA Data Dendritic Cells Dinucleoside Phosphates Disease Drug Targeting Endothelial Cells Enzymes Exhibits Exposure to Formulation Gene Activation Gene Proteins Genetic Polymorphism Goals Human IRF3 gene Immune Immune checkpoint inhibitor Immune response Immune signaling Immunity Immunologics Immunology Immunotherapeutic agent Impairment In Vitro Infection Inflammatory Injections Innate Immune Response Interferon Type I Interferons Lead Ligands Light Liposomes Mediating Microbe Molecular Molecular Biology Mus Myeloid Cells Natural Immunity Outcome Parents Pathway interactions Pattern recognition receptor Penetration Periodicity Phagocytosis Pharmaceutical Preparations Pharmacology Phenotype Positioning Attribute Process Property Proteins Role Signal Transduction Signaling Protein Stimulator of Interferon Genes Stimulus T cell response T-Lymphocyte Therapeutic Tissues Tumor Antigens Tumor Immunity Work adaptive immune response analog anti-tumor immune response antitumor effect base cancer immunotherapy cell killing checkpoint inhibition chemokine comparative cytokine cytosolic receptor gene induction genetic regulatory protein improved in vivo insight macrophage microbial mouse model neoplastic cell novel recruit response small molecule therapy outcome tumor tumor growth tumor microenvironment uptake

项目摘要

PROJECT SUMMARY The goal of this proposal is a molecular and immunological examination of novel compounds that activate innate immune signaling mediated by the proteins cyclic GMP-AMP (cGAMP) synthase (cGAS) and Stimulator of Interferon Genes (STING). Innate immunity is initiated following engagement of pattern recognition receptors by molecules indicative of microbial infection or dying cells. These lead to the orchestration of adaptive immune responses that subsequently eliminate cancerous or infected tissues. cGAMP is the primary activating ligand of STING and its synthesis is triggered by contact between cGAS and cytosolic DNA. Macrophages, dendritic cells (DCs), and endothelial cells are exposed to cytosolic DNA following phagocytosis of material from apoptotic cells including those in the tumor microenvironment. STING-mediated signaling leads to secretion of type I interferons (IFN-I) and proinflammatory cytokines that then activate antigen-presenting cells (APCs), thereby facilitating antigen-directed T-cell killing. STING is, in fact, required for initiating immune responses capable of clearing tumor cells. Intriguingly, pharmacologic activation of STING-dependent processes can lead to spontaneous tumor clearance and even tumor antigen-derived protective immunity in murine models. Numerous efforts are thus focused on understanding the molecular and immunological bases of STING-mediated therapeutic outcomes as well as identifying new molecular entities that can safely elicit these. Our work has identified six small molecular analogs that induce cGAS-mediated synthesis of cGAMP without affecting cytosolic DNA levels. These directly activate STING-dependent phenotypes in both human and murine cells. Moreover, intratumoral administration of the original parent molecule in mouse models of cancer led to impaired tumor growth and prolonged animal survival. We hypothesize that our improved analogs, when paired with formulations optimized for in vivo use, will exhibit enhanced antitumor activity. To our knowledge these represent the first synthetic direct inducers of cGAS-mediated signaling yet described. As such, they are uniquely positioned to establish cGAS (and perhaps STING regulatory proteins in general) as a viable drug target and also reveal new insights into the role of cGAS-STING in antitumor immunity. We thus propose to undertake a penetrative and comparative characterization of the immunological and molecular responses, anti-tumor capacities, and potential adverse effects of our novel cGAS agonist formulations in murine models of cancer. Results will allow a mechanistic assessment to be made of their immunotherapeutic utility, especially in comparison to clinically pursued molecules and in therapies involving combination with checkpoint inhibitors. Our historically collaborative group possesses expertise in innate immunity, molecular biology, T cell immunology, and cancer immunotherapy and is thus well positioned to execute these studies.

项目摘要该提案的目的是对新型化合物的分子和免疫学检查，以激活先天性由蛋白质环状GMP-AMP（CGAMP）合酶（CGA）和刺激剂介导的免疫信号传导干扰素基因（刺）。在通过模式识别受体参与后，先天免疫力是由分子指示微生物感染或垂死细胞。这些导致自适应免疫的编排随后消除癌性或感染组织的反应。 CGAMP是主要的激活配体 CGA与胞质DNA之间的接触触发了STING及其合成。巨噬细胞，树突状细胞（DC）和内皮细胞在吞噬细胞的吞噬作用后暴露于胞质DNA 包括肿瘤微环境中的那些。刺激介导的信号导致I型干扰素的分泌（IFN-I）和促炎细胞因子，然后激活抗原呈递细胞（APC），从而促进抗原指导的T细胞杀戮。实际上，刺激是启动能够清除的免疫反应所必需的肿瘤细胞。有趣的是，依赖刺激过程的药理激活会导致自发在鼠模型中，肿瘤清除率甚至肿瘤抗原衍生的保护性免疫。许多努力因此，专注于理解刺激介导的治疗的分子和免疫碱基结果以及确定可以安全引起这些的新分子实体。我们的工作已经确定了六个诱导CGAS介导的CGAMP合成而不影响胞质DNA水平的小分子类似物。这些直接激活了人类和鼠细胞中的sting依赖性表型。而且，肿瘤内在癌症的小鼠模型中给予原始母体分子导致肿瘤生长受损和长时间的动物生存。我们假设与优化的配方配对时，我们的改进类似物的改进对于体内使用，将表现出增强的抗肿瘤活性。据我们所知，这些代表了第一个合成直接 CGAS介导的信号传导的诱导剂尚未描述。因此，它们是建立CGA的独特位置（也许通常是刺痛的调节蛋白）作为可行的药物靶标，也揭示了对 CGA刺激在抗肿瘤免疫中的作用。因此，我们建议进行渗透和比较免疫和分子反应，抗肿瘤能力以及潜在不利的表征我们新型CGAS激动剂制剂在癌症的鼠模型中的影响。结果将允许机械评估其免疫治疗效用，尤其是与临床追求相比分子和涉及检查点抑制剂组合的疗法。我们历史上的合作小组具有先天免疫，分子生物学，T细胞免疫学和癌症免疫疗法以及因此，可以很好地执行这些研究。