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Principal Investigator: Aaron F Straight
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $475,613
Funding agency: National Cancer Institute
PROJECT SUMMARY
The goal of cancer immunotherapy is to awaken the body’s anti-tumoral immune response to fight against
all cancers in all patients. Our lab recently identified a key mechanism by which cancer cells are detected by our
innate immune system. We now know that cancer cells, with intrinsic chromosomal instability, constantly secret
the soluble small molecule 2’3’-cyclic-GMP-AMP (cGAMP). Acting as an immunotransmitter, extracellular
cGAMP is taken up by surrounding tissues and immune cells to activate its receptor STING in a paracrine fashion,
resulting in downstream anti-cancer immune responses. The importance of extracellular cGAMP is demonstrated
by our finding that it is required for the curative effect of ionizing radiation in a murine model of breast cancer.
Furthermore, we identified the extracellular enzyme ENPP1 as the only detectable hydrolase of extracellular
cGAMP that blocks its signaling pathway. Therefore, we hypothesize that ENPP1 is an innate immune
checkpoint that could be targeted to expand the reach of cancer immunotherapy.
Although ENPP1 is cGAMP’s only hydrolase, it hydrolyzes extracellular ATP at comparable potency.
Therefore, genetic and pharmacological tools that are based on complete ablation of ENPP1 activity cannot be
used to distinguish the physiological role between extracellular cGAMP and ATP. Here, we propose selective
genetic and chemical biology approaches: we will characterize genetic tools that selectively abolish ENPP1’s
hydrolase activity toward extracellular cGAMP but not ATP (dENPP1cGAMP); in parallel we will develop substrate-
specific ENPP1 inhibitors as tool compounds and potential immunotherapeutics.
In Aim 1, we will fully characterize the kinetics, selectivity, and mechanisms of action of mutant
dENPP1cGAMP, as well as the pathophysiology of dEnpp1cGAMP mice. In Aim 2, we will evaluate multiple tumor
models in the dEnpp1cGAMP mouse strain to determine the physiological roles of extracellular cGAMP in
controlling tumor growth and synergism with checkpoint blockers. In Aim 3, we will first characterize mechanism
of substrate selectivity of our lead cGAMP-selective ENPP1 inhibitor and then use this inhibitor to harness the
anti-tumoral effects of extracellular cGAMP. This proposal combines careful biochemical analyses with mouse
genetics and tool compound development to address the role of extracellular cGAMP in cancer, with the goal of
improving cancer immunotherapy.
Terms: <ATP Hydrolysis><Ablation><Address><Advanced Cancer><Advanced Malignant Neoplasm><Atlas of Cancer Mortality in the United States><Binding><Biochemical><Biology><Body Tissues><Breast Cancer Model><Breast tumor model><Cancer Maps><Cancer Model><Cancer Treatment><CancerModel><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chemicals><Chromosomal Instability><Chromosome Instability><Cyclic GMP><DNA Binding><DNA Binding Interaction><DNA Damage><DNA Injury><DNA bound><Dendritic Cells><Detection><Development><Double-Stranded DNA><Dysfunction><Enzyme Gene><Enzymes><Exhibits><Functional disorder><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Goals><Guanosine Cyclic Monophosphate><Hydrolase><Hydrolase Family Gene><Hydrolase Gene><Hydrolysis><Immune><Immune Cell Activation><Immune response><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunotherapeutic agent><In Vitro><Infiltration><Innate Immune System><Innate Immunity><Interferon Type I><Intracellular Communication and Signaling><Intracellular Second Messenger><Ionizing Electromagnetic Radiation><Ionizing radiation><Kinetics><Knock-out><Knockout><Lead><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Membrane><Mice><Mice Mammals><Modeling><Molecular><Molecular Interaction><Mouse Strains><Murine><Mus><Mutation><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Pathway interactions><Patients><Pb element><Physiologic><Physiological><Physiology><Physiopathology><Play><Point Mutation><Production><Radiation-Ionizing Total><Receptor Protein><Role><Second Messenger Systems><Second Messengers><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Structure-Activity Relationship><Substrate Specificity><Testing><Tissues><Tumor Immunity><Tumor Promotion><Veiled Cells><analog><anti-cancer><anti-cancer immunotherapy><anti-cancer therapy><anti-tumor effect><anti-tumor immune response><anti-tumor immunity><anticancer immunotherapy><antitumor effect><antitumor immunity><biological signal transduction><cGMP><cancer cell><cancer immunity><cancer immunotherapy><cancer microenvironment><cancer therapy><cancer type><cancer-directed therapy><check point blocker><checkpoint blockers><chemical structure function><developmental><drug development><ds-DNA><dsDNA><extracellular><fighting><genome mutation><heavy metal Pb><heavy metal lead><host response><immune activation><immune check point blocker><immune checkpoint blockers><immune drugs><immune system response><immune-based cancer therapies><immune-based therapeutics><immunologic therapeutics><immunoresponse><immunotherapeutics><immunotherapy agent><immunotherapy for cancer><immunotherapy of cancer><improved><in vivo><inhibitor><innate check point><innate checkpoint><innate immune check point><innate immune checkpoint><innate immunity checkpoint><ionizing output><malignancy><mammary cancer model><mammary tumor model><membrane structure><mouse genetics><mouse model><murine model><mutant><neoplasm/cancer><nucleoside triphosphate><overexpress><overexpression><pancreatic cancer model><pancreatic tumor model><paracrine><pathophysiology><pathway><pharmacologic><prevent><preventing><receptor><response><side effect><signal transduction second messengers><small molecule><social role><standard of care><structure function relationship><synergism><tool><tumor><tumor growth><tumor microenvironment>