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Principal Investigator: Jinming Gao
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $984,000
Funding agency: National Cancer Institute
Abstract
Host defense responses by the mammalian immune system can be very potent but require
exquisite spatio-temporal coordination. This coordination is essential to match the immune activity
to the specific threat, to monitor and regulate the immune response, minimize damage to normal
tissues, and terminate the response when the hazard is eliminated. Stimulator of interferon genes
(STING) is an endoplasmic reticulum-associated signaling protein that is essential for
transcriptional regulation of numerous host defense genes against malignant cells. STING is
activated by 2’, 3’-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), an
endogenous secondary messenger, which is produced by cGAMP synthase (cGAS) in response
to cytosolic DNA as a danger signal. Despite potent antitumor activities demonstrated by STING
agonists in preclinical studies, early clinical trials have yet to show significant antitumor response
in cancer patients. Current STING agonist designs are ‘always ON’, leading to on-target, off-tumor
toxicity in healthy tissues. The proposed R35 program will integrate four areas of research to
harness this important natural defense mechanism and innovate a safe and efficacious STING-
targeted therapy for immune-resistant cancers. In nanotechnology, we will design and synthesize
a (pH-hypoxia) AND logic nanoparticle STING agonist that stays protected in normal tissues but
will be activated in response to acidic pH and hypoxia signals inherent in the tumor
microenvironment. This ensures minimal toxicity in healthy tissues, while promoting targeted
STING activation within malignancies. In STING signaling, we will employ cryo-electron
microscopy to investigate the synergy of PSC7A with cGAMP for STING binding and activation.
In dendritic cell biology, we will investigate STING-mediated transformation of hematopoietic
progenitor cells into conventional type 1 dendritic cells (cDC1), and define its ramifications on
antitumor immunity. In immune-oncology, we will employ patient-derived tumor fragments to probe
into STING agonists' roles in immune resistant tumors. Furthermore, we will assess the prognostic
value of the STING-cDC1 signature in forecasting therapeutic responses to treatments like
STING-targeted interventions and checkpoint blockade therapies. Through our bench-to-clinic
and back-to-bench approach, our goal is to pinpoint the barriers that have stymied effective
targeting of this crucial biological pathway, and ultimately apply these insights to establish a
successful STING-targeted therapy in cancer patients unresponsive to current treatments.
Terms: <5'-Adenylic acid><Adenosine Monophosphate><Adenylic Acid><Agonist><Antitumor Response><Area><Back><Binding><Biological><Blood Precursor Cell><Body Tissues><Cancer Patient><Cancers><Cell Communication and Signaling><Cell Signaling><Cellular biology><Clinical><Cryo-electron Microscopy><Cryoelectron Microscopy><Cyclic GMP><DNA><Defense Mechanisms><Dendritic Cells><Deoxyribonucleic Acid><Dorsum><Electron Cryomicroscopy><Endoplasmic Reticulum><Engineering><Ensure><Ergastoplasm><Gene Activation><Gene Targeting><Genes><Goals><Guanosine Cyclic Monophosphate><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Host Defense><Hypoxia><Hypoxic><Immune><Immune response><Immune system><Immunes><Immunity><Immunological response><Immunooncology><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Logic><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mediating><Molecular><Molecular Interaction><Monitor><Nanotechnology><Normal Tissue><Normal tissue morphology><Oxygen Deficiency><Pathway interactions><Patients><Research><Role><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Stimulator of Interferon Genes><Technology><Tissues><Toxic effect><Toxicities><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Tumor Escape><Tumor Immune Escape><Tumor Immunity><Veiled Cells><anti-tumor immunity><anti-tumor response><antitumor immunity><bench bed side><bench bedside><bench to bed side><bench to bedside><bench to clinic><bench to clinical practice><biologic><biological signal transduction><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><cGMP><cancer cell><cancer evasion><cancer immune escape><cancer immune evasion><cancer immunity><cancer microenvironment><cell biology><check point blockade><checkpoint blockade><cryo-EM><cryoEM><cryogenic electron microscopy><cyclic GMP-AMP synthase/STING><defense response><design><designing><early clinical trial><early phase clinical trial><engineered immune system><gene-based treatment><gene-directed therapy><gene-targeted therapy><gene-targeted treatment><hazard><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><host response><immune check point blockade><immune checkpoint blockade><immune engineering><immune resistance><immune system response><immune-oncology><immune-resistant><immuno oncology><immunoengineering><immunology oncology><immunoresistance><immunoresponse><innovate><innovation><innovative><insight><interventional strategy><malignancy><nano particle><nano tech><nano technology><nano-sized particle><nano-technological><nanoparticle><nanosized particle><nanotech><nanotechnological><neoplasm/cancer><oncoimmunology><pathway><physiological defense response><pre-clinical study><preclinical study><prognostic ability><prognostic power><prognostic utility><prognostic value><programs><psychological defense mechanism><refractory cancer><resistant cancer><response><response to therapy><response to treatment><social role><spatiotemporal><synergism><therapeutic response><therapy response><treatment response><treatment responsiveness><tumor><tumor evasion><tumor immune evasion><tumor microenvironment>