Anti-tumor efficacy of novel cGAS-STING pathway agonists

新型 cGAS-STING 通路激动剂的抗肿瘤功效

• 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
• 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

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.

项目概要 该提案的目标是对激活先天性的新型化合物进行分子和免疫学检查 由蛋白质环 GMP-AMP (cGAMP) 合酶 (cGAS) 和刺激物介导的免疫信号传导 干扰素基因（STING）。先天免疫是在模式识别受体参与后启动的 指示微生物感染或死亡细胞的分子。这些导致了适应性免疫的协调 随后消除癌变或感染组织的反应。 cGAMP 是主要激活配体 STING 及其合成是由 cGAS 和胞质 DNA 之间的接触触发的。巨噬细胞、树突状细胞 (DC) 和内皮细胞在吞噬凋亡细胞物质后暴露于胞质 DNA 包括肿瘤微环境中的那些。 STING 介导的信号传导导致 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 抗原导向的 T 细胞杀伤。事实上，STING 是启动能够清除病毒的免疫反应所必需的。 肿瘤细胞。有趣的是，STING 依赖性过程的药理学激活可以导致自发性 小鼠模型中的肿瘤清除甚至肿瘤抗原衍生的保护性免疫。无数的努力正在 因此专注于了解 STING 介导的治疗的分子和免疫学基础 结果以及识别可以安全引发这些结果的新分子实体。我们的工作确定了六 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。 这些直接激活人类和小鼠细胞中的 STING 依赖性表型。此外，瘤内 在小鼠癌症模型中施用原始母体分子会导致肿瘤生长受损， 延长动物的生存时间。我们假设我们改进的类似物与优化的配方搭配使用时 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的直接 cGAS 介导的信号传导诱导剂尚未描述。因此，他们在建立 cGAS 方面具有独特的优势 （也许还有一般的 STING 调节蛋白）作为可行的药物靶点，也揭示了对 cGAS-STING 在抗肿瘤免疫中的作用。因此，我们建议进行一项渗透性和比较性的研究。 免疫学和分子反应、抗肿瘤能力和潜在不良反应的表征 我们的新型 cGAS 激动剂制剂对小鼠癌症模型的影响。结果将允许机械 对它们的免疫治疗效用进行评估，特别是与临床追求的比较 分子以及涉及与检查点抑制剂联合的疗法。我们历史悠久的合作团队 拥有先天免疫、分子生物学、T细胞免疫学和癌症免疫治疗方面的专业知识 因此，我们有能力开展这些研究。