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Principal Investigator: Judith A VARNER
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $509,078
Funding agency: National Cancer Institute
Lung cancer is one of the most lethal of solid tumors. The overall survival rate for patients with lung cancer
remains low, at 21%. As 236,740 new cases of lung cancer and 130,180 deaths are expected in 2022, there
remains a pressing need to advance research into new therapeutic approaches for the treatment of lung cancer.
Solid tumors, such as lung tumors, are laden with abundant, tumor-promoting macrophages, monocytes and
granulocytes. These innate immune cells promote tumor progression through profound inhibition of T cell
recruitment and activation and through stimulation of tumor angiogenesis, stemness, drug resistance and
metastasis. Strategies that reduce the accumulation of myeloid cells or alter their functional properties
significantly slow or eliminate tumor progression in animal models of cancer and synergize with other therapeutic
approaches to improve cancer outcomes. We previously discovered that a myeloid cell specific isoform of
phosphatidylinositol-4,5-bisphosphate 3-kinase, PI3Kgamma (PI3Kg), controls both myeloid cell
accumulation and immune suppressive polarization in tumors. Genetic or pharmacological inactivation of PI3Kg,
but not other PI3K isoforms, reduces myeloid cell accumulation in tumors and alters the transcriptional profile of
immune suppressive, pro-angiogenic tumor associated macrophages (TAMs) toward a pro-inflammatory, anti-
tumor phenotype. We have found that PI3Kg inhibition synergizes with chemotherapy and with checkpoint
inhibitors to activate memory T cells and reduce tumor growth in models of lung cancer, breast cancer,
melanoma, head and neck cancer and glioblastoma. Based on our findings, the PI3Kg inhibitor, IPI-549
(eganelisib), was developed as an immune oncology therapeutic. We identified signatures of re-activated
adaptive immune responses in tumor tissues from lung cancer patients who participated in IPI-549 Phase 1
clinical trials, indicating that PI3Kg blockade can re-awaken anti-tumor immunity in human tumors and thus may
provide therapeutic benefit to lung cancer patients. However, we also identified pathways of resistance to
therapy, indicating that further dissection of the roles that PI3Kg and its inhibitors play in lung tumors is warranted.
The exact biochemical and cellular mechanisms by which PI3Kg inhibits anti-tumor immunity in murine and
human lung cancer remain unclear. Deciphering these mechanisms will provide new therapeutic insights into
the mechanisms of tumor immune suppression. Therefore, we propose studies to determine which molecular
and cellular mechanisms are direct and indirect targets of PI3Kg mediated immune suppression, to identify and
treat pathways of resistance to PI3Kg inhibitor therapy and to evaluate the impact of PI3Kg inhibition on immune
responses in mouse and human models of NSCLC. The specific aims to accomplish these goals are: 1) To
delineate molecular mechanisms by which PI3Kg regulates macrophage transcription; 2) To determine
mechanisms by which PI3Kg controls lung tumor progression in vivo; 3) To discover and target mechanisms of
resistance to PI3Kg inhibition in lung carcinoma.
Terms: <1-Phosphatidylinositol 3-Kinase><Accounting><After Care><After-Treatment><Aftercare><Animal Cancer Model><Antibodies><Antigen Presentation><Biochemical><Biological><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood granulocytic cell><Blood monocyte><Breast Cancer><Cancer Patient><Cancers><Cell Body><Cell Communication and Signaling><Cell Function><Cell Growth in Number><Cell Multiplication><Cell Physiology><Cell Process><Cell Proliferation><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Proliferation><Cessation of life><Checkpoint inhibitor><Clinic><Clinical><Clinical Trials><Death><Dendritic Cells><Disease><Disease-Free Survival><Disorder><Dissection><Drug resistance><Early Diagnosis><Early treatment><Early-Stage Clinical Trials><Event-Free Survival><Expression Signature><Gene Expression Profile><Gene Transcription><Generalized Growth><Genetic><Genetic Transcription><Glioblastoma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Granular Leukocytes><Granulocytic cell><Growth><Head and Neck Cancer><Head and Neck Carcinoma><Human><Immune><Immune Cell Activation><Immune checkpoint inhibitor><Immune response><Immunes><Immunological response><Immunooncology><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Inflammation><Inflammatory><Intracellular Communication and Signaling><Invaded><Isoforms><Kinases><Lung Carcinoma><Lung Neoplasms><Lung Tumor><Macrophage><Malignant Breast Neoplasm><Malignant Head and Neck Neoplasm><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Marrow Neutrophil><Marrow monocyte><Mediating><Melanoma><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Myeloid Cells><Mφ><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Neoplasm Metastasis><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Operative Procedures><Operative Surgical Procedures><Outcome><PI-3 Kinase><PI3-Kinase><PI3CG><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><PIP2><Pathway interactions><Patients><Phase 1 Clinical Trials><Phase I Clinical Trials><Phenotype><Phosphatidylinositol 3-Kinase><Phosphatidylinositol 4,5-Biphosphate><Phosphatidylinositol 4,5-Diphosphate><Phosphatidylinositol-3-OH Kinase><Phosphatidylinositol-4,5-Bisphosphate><Phosphoinositide 3-Hydroxykinase><Phosphotransferase Gene><Phosphotransferases><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Property><Protein Isoforms><PtIns 4,5-P2><PtdIns 3-Kinase><PtdInsP2><Pulmonary Cancer><Pulmonary Neoplasms><Pulmonary malignant Neoplasm><RNA Expression><Regulation><Research><Resected><Resistance><Role><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Solid Neoplasm><Solid Tumor><Stem Cell like><Subcellular Process><Surgical><Surgical Interventions><Surgical Procedure><Survival Rate><T memory cell><T-Cells><T-Lymphocyte><Testing><Therapeutic><Tissue Growth><Transcription><Transphosphorylases><Tumor Angiogenesis><Tumor Cell><Tumor Immunity><Tumor Promotion><Tumor Tissue><Tumor-associated macrophages><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><Veiled Cells><adaptive immune response><adaptive immunity><antagonism><antagonist><anti-tumor immune response><anti-tumor immunity><antitumor immunity><biologic><biological signal transduction><cancer immunity><cancer metastasis><cancer microenvironment><cancer progression><cell type><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><chemotherapy><disease model><disorder model><drug resistant><early detection><early therapy><gene expression pattern><gene expression signature><glioblastoma multiforme><granulocyte><head/neck cancer><host response><human model><immune activation><immune check point inhibitor><immune check point therapy><immune checkpoint therapy><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune-oncology><immuno oncology><immunology oncology><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><in vivo><inhibitor><inhibitor drug><inhibitor therapeutic><inhibitor therapy><innovate><innovation><innovative><insight><lung cancer><malignancy><malignant breast tumor><malignant head and neck tumor><memory T lymphocyte><model of human><monocyte><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><neutrophil><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapeutics><new therapy><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><next generation therapeutics><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy approach><novel therapy target><oncoimmunology><ontogeny><pathway><pharmacologic><phase 2 trial><phase I protocol><phase II trial><post treatment><prevent><preventing><recruit><resistance mechanism><resistance to Drug><resistance to therapy><resistant><resistant mechanism><resistant to Drug><resistant to therapy><social role><spongioblastoma multiforme><stem cell characteristics><stemness><surgery><synergism><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapy resistant><thymus derived lymphocyte><trafficking><transcriptional profile><transcriptional signature><treatment resistance><tumor><tumor cell metastasis><tumor growth><tumor microenvironment><tumor progression>