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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.

项目总结