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

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

项目成果

期刊论文数量(0)
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VICTOR Robert DEFILIPPIS其他文献

VICTOR Robert DEFILIPPIS的其他文献

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{{ truncateString('VICTOR Robert DEFILIPPIS', 18)}}的其他基金

A Self-Adjuvanting Virus Like Particle Vaccine Platform for Emerging Viruses
针对新兴病毒的自我佐剂病毒样颗粒疫苗平台
  • 批准号:
    10711617
  • 财政年份:
    2023
  • 资助金额:
    $ 19.45万
  • 项目类别:
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:
    10430274
  • 财政年份:
    2021
  • 资助金额:
    $ 19.45万
  • 项目类别:
Mechanistic Exploration of cGAS-STING-Mediated Vaccine Enhancement
cGAS-STING 介导的疫苗增强机制探索
  • 批准号:
    10318966
  • 财政年份:
    2019
  • 资助金额:
    $ 19.45万
  • 项目类别:
Mechanistic Exploration of cGAS-STING-Mediated Vaccine Enhancement
cGAS-STING 介导的疫苗增强机制探索
  • 批准号:
    10534676
  • 财政年份:
    2019
  • 资助金额:
    $ 19.45万
  • 项目类别:
THE ROLE OF CYTOMEGALOVIRUS PHOSPHOPROTEIN 65 IN VIRUS REPLICATON IN VIVO
巨细胞病毒磷酸蛋白65在体内病毒复制中的作用
  • 批准号:
    7958465
  • 财政年份:
    2009
  • 资助金额:
    $ 19.45万
  • 项目类别:
THE ROLE OF CYTOMEGALOVIRUS PHOSPHOPROTEIN 65 IN VIRUS REPLICATON IN VIVO
巨细胞病毒磷酸蛋白65在体内病毒复制中的作用
  • 批准号:
    7715956
  • 财政年份:
    2008
  • 资助金额:
    $ 19.45万
  • 项目类别:
THE ROLE OF CYTOMEGALOVIRUS PHOSPHOPROTEIN 65 IN VIRUS REPLICATON IN VIVO
巨细胞病毒磷酸蛋白65在体内病毒复制中的作用
  • 批准号:
    7561989
  • 财政年份:
    2007
  • 资助金额:
    $ 19.45万
  • 项目类别:

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