Samuel J. Hobbs, PhD, Postdoctoral Fellow Dana-Farber Cancer Institute Area of Research: All Cancers Therapeutic approaches that enhance the antitumor immune response are among the most effective forms of treatment in the fight against cancer. The cellular enzyme cyclic GMP-AMP synthase (cGAS) is an immune sensor protein that detects pathogen- or tumor-derived DNA. Upon binding DNA, cGAS activates an innate immune pathway by rapidly synthesizing a small signaling molecule called cGAMP (cyclic GMP-AMP), which binds to the receptor STING to drive expression of immune-related genes. The cGAS-STING pathway has emerged as a key player in antitumor immunity, and therapies aimed at activating STING are among the most promising immunotherapeutics currently in development. The vast majority of tumor cells retain high expression of both cGAS and STING, suggesting that tumor cells actively degrade cGAMP to counteract the antitumor effects of cGAS- STING immunity. Critically, there are currently no known mechanisms that regulate the stability of cGAMP within cells under healthy conditions. This lack of understanding limits the ability to understand how tumors co-opt this regulatory pathway to avoid antitumor immunity and prevents development of therapeutics to enhance or inhibit this pathway. With support from CRI, Dr. Hobbs will identify novel genes that regulate the stability of cGAMP and define the mechanisms governing degradation of this potent immune signaling molecule. These findings have the potential to uncover a completely novel immunotherapy target and could enable the rational design of metabolically stable drugs that promote antitumor immunity. Projects and Grants Role of 2′3′-cGAMP stability and spread in antitumor immunity Dana-Farber Cancer Institute | All Cancers | 2021 | Philip Kranzusch, PhD
