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Principal Investigator: Zihai Li
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2024
Award: $521,454
Funding agency: National Cancer Institute
PROJECT SUMMARY
As a ubiquitous HSP90 paralog in the endoplasmic reticulum (ER), GRP94 plays important roles in protein quality
control in the secretory pathway by participating in both the unfolded protein response and the ER-associated
protein degradation pathway. My laboratory has demonstrated that GRP94 is a strategically important target for
cancer, because it controls multiple key molecular pathways in cell growth, migration, immune tolerance and
differentiation, including integrins, TLRs, IGF-II, Wnt co-receptor LRP6, and GARP (or LRRC32). GARP
(Glycoprotein A Repetitions Predominant) is responsible for surface docking and activation of latent TGFb and
a focus of this proposal We have made significant contributions to this area through immunological and
biochemical studies, including: 1) that GARP is an important molecule for cancer immune evasion via regulating
multiple cell types (e.g., cancer cells, platelets, regulatory T cells, B cells). 2) We discovered a novel mechanism
of TGFb activation from cell surface GARP-TGFb complex via proteolytic cleavage of GARP. 3) GARP has been
found to be aberrantly expressed in multiple human cancers to promote oncogenesis via both cancer cell-intrinsic
and -extrinsic mechanisms. 4) Preclinical studies suggest that GARP is a novel therapeutic target for cancer
immunotherapy. These accomplishments have deepened our conviction that the study of GRP94 and its client
network will lead to better understanding of this chaperone biology in cancer and to development of novel cancer
therapeutics, alone or in combination with approved immunotherapeutic agents. In the next phase of the study,
we will address the hypothesis that GRP94/GARP-targeted therapy applied to multiple vulnerable cancers will
overcome immune resistance to checkpoint inhibitors.
First, we will determine the roles and molecular mechanism involved in GRP94 regulation of TGFb biogenesis,
activation and signaling. This aim will focus on structural analysis of the GRP94-GARP complex, and on resolving
mechanisms of GRP94 in folding two other molecules important in regulating TGFb signaling: LRRC33 and
LRG1. Second, we will develop novel cancer immunotherapeutic strategies targeting GRP94 and GARP. The
goal is to advance the top first-in-class agent(s) among several pre-clinical leads through a milestone-driven
strategy. This includes agents to inhibit GARP cleavage, GARP-specific antibodies, drug-like GRP94-selective
inhibitors, antibodies against the cell surface GRP94 (ectoGRP94) preferentially expressed on cancer cells, and
T cells engineered to express chimeric antigen receptor (CAR) composed of a single-chain antibody against
ectoGRP94 fused with T cell signaling motifs (GRP94-CAR-T). Overall, the impact of this study lies in
fundamental understanding of GRP94 in regulating the TGFb pathway and in developing promising next
generation immunotherapeutic agents.
Terms: <Address><Antibodies><Area><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Biochemical><Biogenesis><Biology><Blood Platelets><Bone-Derived Transforming Growth Factor><Cancer Biology><Cancer Control><Cancer Control Science><Cancer Treatment><Cancers><Cell Communication and Signaling><Cell Signaling><Cell Surface Glycoproteins><Cell surface><Cellular Expansion><Cellular Growth><Chaperone><Checkpoint inhibitor><Client><Clinical><Clinical Trials><Collaborations><Complex><D11S833E><Degradation Pathway><Degradative Pathway><Development><Docking><Drugs><Endoplasmic Reticulum><Eragrostis><Ergastoplasm><F8VWF><Foundations><GARP gene><GARP protein><GRP94><Glycoprotein A Repetitions Predominant><Goals><Growth Factor Receptors><HSP-90><HSP90><Heat-Shock Proteins 90><Human><IGF-1><IGF-2><IGF-I><IGF-I-SmC><IGF-II><Immune><Immune Tolerance><Immune checkpoint inhibitor><Immune mediated therapy><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunologic Tolerance><Immunological><Immunologically><Immunologically Directed Therapy><Immunologics><Immunotherapeutic agent><Immunotherapy><Insulin-Like Growth Factor 1><Insulin-Like Growth Factor 2><Insulin-Like Growth Factor I><Insulin-Like Growth Factor II><Insulin-Like Somatomedin Peptide I><Insulin-Like Somatomedin Peptide II><Integrins><Integrins Extracellular Matrix><Intracellular Communication and Signaling><LRR protein><LRRC32><LRRC32 gene><Laboratories><Leucine-Rich Repeat-Containing Protein 32><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Manuscripts><Marrow platelet><Mediating><Medication><Membrane Glycoproteins><Metabolic Protein Degradation><Milk Growth Factor><Modern Man><Molecular><Molecular Chaperones><Molecular Interaction><Multiplication-Stimulating Activity><Multiplication-Stimulating Factor><Myelogenous><Myeloid><Nature><Oncogenesis><Oncogenic><Origin of Life><PD-1/PD-L1><PD-1/PDL1><PD1-PD-L1><PD1/PD-L1><PD1/PDL1><Pathway interactions><Pharmaceutical Preparations><Phase><Platelet Transforming Growth Factor><Platelets><Play><Pre-Clinical Model><Preclinical Models><Protein Turnover><Proteins><Publishing><Quality Control><Receptor Protein><Regulation><Regulatory Protein Degradation><Regulatory T-Lymphocyte><Renaissance><Resistance><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Somatomedin A><Somatomedin C><Somatomedin MSA><Structural Biologist><Suppressor Cells><Suppressor-Effector T-Cells><Suppressor-Effector T-Lymphocytes><Surface><Surface Glycoproteins><T Suppressor Cell><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell targeted therapeutics><T cell therapy><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Teff><Teff cell><Therapeutic><Thrombase><Thrombin><Thrombocytes><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Translational Research><Translational Science><Treg><Tumor Escape><Tumor Immune Escape><VWF gene><adoptive T cell transfer><adoptive T-cell therapy><anti-cancer><anti-cancer immunotherapy><anti-cancer therapy><anticancer immunotherapy><biological signal transduction><cancer cell><cancer evasion><cancer immune escape><cancer immune evasion><cancer immune therapeutics><cancer immunotherapeutics><cancer immunotherapy><cancer microenvironment><cancer therapy><cancer-directed therapy><cell growth><cell type><chimeric antigen receptor><convict><design><designing><developmental><drug/agent><effector T cell><engineered T cells><fibrinogenase><genetic approach><genetic strategy><genetically engineered T-cells><hsp90 Family><immune check point><immune check point inhibitor><immune checkpoint><immune drugs><immune resistance><immune system tolerance><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune unresponsiveness><immune-based cancer therapies><immune-based therapeutics><immune-based therapies><immune-based treatments><immune-resistant><immunecheckpoint><immuno therapy><immunologic therapeutics><immunological paralysis><immunoresistance><immunotherapeutics><immunotherapy agent><immunotherapy for cancer><immunotherapy of cancer><inhibitor><insight><leucine-rich repeat protein><malignancy><migration><neoplasm/cancer><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><overexpress><overexpression><paralog><paralogous gene><pathway><pre-clinical><pre-clinical study><preclinical><preclinical study><protein degradation><receptor><regulatory T-cells><resistant><response><side effect><social role><suppressor T lymphocyte><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic T-cell platform><thymus derived lymphocyte><transgenic T- cells><translation research><translational investigation><tumor evasion><tumor immune evasion><tumor microenvironment><tumorigenesis><vWF>