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Principal Investigator: Jin Chen
Organization: VETERANS HEALTH ADMINISTRATION
Fiscal Year: 2024
Funding agency: Veterans Affairs
Project Summary/Abstract
Lung cancer is the leading cause of cancer-related deaths in the US and disproportionally affects
Veterans. Although targeted therapies for lung adenocarcinoma improve overall survival, no similar
advances have been made in lung squamous carcinoma (LUSC), which represents 30% of cases,
strongly associated with smoking, and highly metastatic. In contrast, immune checkpoint inhibitor
therapy has some success in treating LUSC patients. However, majority of patients do not respond to
such treatment. Thus, there is an unmet clinical need to better understand LUSC and develop new
treatments in this subclass of lung cancer that is refractory to molecular targeted therapies.
In searching for vulnerabilities in squamous lung cancer, we recently re-analyzed TCGA LUSC
datasets. We found that while individual driver mutations are rare, PIK3CA mutation/amplification,
PTEN deletion, and RICTOR amplification combined accounts for more than 40% of the LUSC
tumors. As both PI3K and PTEN regulates PIP3 levels, which activates mTORC2 and AKT, these
findings indicate that PI3K-AKT pathway is hyperactive, and targeting mTORC2 may inhibit the entire
pathway in the LUSC tumors.
In this application, we discovered that mTORC2 loss-of-function (LOF) significantly altered tumor
metabolism, inhibited tumor growth in vivo, and impacted antitumor immune environment. Further, we
found that selective inhibition of mTORC1 in vascular endothelium increases tumor infiltrating
lymphocytes. Thus, the combination of endothelial mTORC1 inhibition coupled with tumor inhibition
of mTORC2 will create a favorable microenvironment for anti-tumor immunity, enhancing T-cell
recruitment (mTORC1) and activity (mTORC2), providing a targeted therapy treatment strategy for
LUSC. In Aim 1, we will investigate the effects of mTORC2 inhibition on antitumor immune
microenvironment. In Aim 2, we will investigate the role of endothelial mTORC1 on recruiting LUSC
infiltrating T cells. In Aim 3, we propose (i) to increase tumor infiltrating lymphocytes by low-dose
RAD001 (selective inhibition of mTORC1 in endothelium) and (ii) improve T cell effector function by
siRictor nanoparticles (NP) (inhibition of mTORC2) in LUSC, either as a single agent, in combination
with checkpoint inhibitors, or three-way combination of low-dose RAD001 to increase TILs, followed
by siRictor-NPs and anti-PD1.
Success of this project will improve our understanding of the molecular mechanisms of initiation and
progression to lung squamous cancer, especially how mTORC2 signaling in tumor cells influences
immune microenvironment. Study of immune microenvironment is particularly important for LUSC, as
immunotherapy becomes one main treatment for these patients. Further, success of this project will
have significant translational potential, as nanoparticle strategy is used in recent COVID-19 vaccines.
The proposed studies in this application will provide proof-of-concept for the impact of inhibiting
mTORC2 using a nanoparticle on tumor growth and antitumor immune responses.
Terms: <1-Phosphatidylinositol 3-Kinase><2019-nCoV vaccine><AKT><Affect><Age><Akt protein><Armed Forces Personnel><B7-H1><B7H1><Blood Vessels><CD152><CD152 Antigen><CD152 Gene><CD162 antigen><CD274><COVID-19 vaccine><CTLA 4><CTLA-4 Gene><CTLA4><CTLA4 gene><CTLA4-TM><Cancer Cause><Cancer Etiology><Cancers><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Function><Cell Locomotion><Cell Migration><Cell Movement><Cell Physiology><Cell Process><Cell Signaling><Cell surface><Cells><Cellular Function><Cellular Migration><Cellular Motility><Cellular Physiology><Cellular Process><Cessation of life><Checkpoint inhibitor><Chemical Exposure><Clinical><Complex><Coupled><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><Data><Data Set><Death><Disease><Disorder><Dose><Endothelium><Environment><Epidermoid Carcinoma><Epidermoid Cell Lung Carcinoma><Feedback><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Goals><Hyperactivity><Immune><Immune Modulation Therapy><Immune checkpoint inhibitor><Immune mediated therapy><Immunes><Immunofluorescence><Immunofluorescence Immunologic><Immunologically Directed Therapy><Immunotherapy><In Situ><Individual><Infiltration><Intracellular Communication and Signaling><Kinases><Lewis Lung Carcinoma><Ligands><Lung Adenocarcinoma><MMAC1><MMAC1 protein><Macrophage><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediator><Medicine><Military><Military Personnel><Molecular><Mutated in Multiple Advanced Cancers 1><Mutation><Mφ><Nutrient><Oncogenic><P-selectin glycoprotein ligand-1><P-selectin ligand protein><PD 1><PD-1><PD-L1><PD1><PDL-1><PDL1><PHTS gene><PHTS protein><PI-3 Kinase><PI3-Kinase><PI3CG><PI3K-Alpha><PI3KGamma><PI3k><PIK3><PIK3-Alpha><PIK3CA><PIK3CA gene><PIK3CG><PIK3CG gene><PSGL-1><PTEN><PTEN gene><PTEN protein><PTEN1><Pathway interactions><Patients><Phase 2 Clinical Trials><Phase II Clinical Trials><Phosphatase and Tensin Homolog><Phosphatase and Tensin Homolog Deleted on Chromosome 10><Phosphatidylinositol 3-Kinase><Phosphatidylinositol 3-Kinase, Catalytic, 110-kD, Alpha><Phosphatidylinositol 3-Kinase, Catalytic, Alpha><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Phosphotransferase Gene><Phosphotransferases><Pinocytosis><Planocellular Carcinoma><Play><Position><Positioning Attribute><Production><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Protein Kinase B><Proto-Oncogene Proteins c-akt><PtdIns 3-Kinase><Pulmonary Cancer><Pulmonary malignant Neoplasm><RAC-PK protein><Refractory><Research><Resistance><Role><SARS-CoV-2 vaccine><SARS-coronavirus-2 vaccine><Services><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccine><Signal Transduction><Signal Transduction Systems><Signaling><Smoking><Squamous Carcinoma><Squamous Cell Epithelioma><Squamous Cell Lung Carcinoma><Squamous cell carcinoma><Squamous cell lung cancer><Stress><Subcellular Process><T cell infiltration><T-Cells><T-Lymphocyte><TCGA><Teff cell><Testing><The Cancer Genome Atlas><Transphosphorylases><Tumor Cell><Tumor Immunity><Tumor-Infiltrating Lymphocytes><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><Vascular Endothelial Cell><Vascular Endothelium><Veterans><Visualization><War><aPD-1><aPD1><ages><anti programmed cell death 1><anti-PD-1><anti-PD1><anti-programmed cell death protein 1><anti-tumor immune response><anti-tumor immunity><anti-viral immunity><antiPD-1><antiPD1><antitumor immunity><antiviral immunity><biological signal transduction><c-akt protein><cancer cell metabolism><cancer immunity><cancer metabolism><cell motility><check point blockade><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point receptors><check point therapy><checkpoint blockade><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint receptors><checkpoint therapy><chemotherapy><coronavirus disease 2019 vaccine><coronavirus disease-19 vaccine><cytotoxic T-lymphocyte antigen 4><driver lesion><driver mutation><effector T cell><genome mutation><immune check point><immune check point blockade><immune check point inhibitor><immune check point therapy><immune checkpoint><immune checkpoint blockade><immune checkpoint therapy><immune microenvironment><immune modulating therapies><immune modulatory therapies><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immune-modulation treatment><immunecheckpoint><immuno therapy><immunomodulation therapy><immunomodulation treatment><immunomodulator therapies><immunomodulator treatment><immunomodulator-based therapies><immunomodulatory therapies><immunomodulatory therapy><immunomodulatory treatment><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><improved><in vivo><inhibitor><interstitial><loss of function><lung cancer><lung squamous cancer><lung squamous carcinoma><lung squamous cell carcinoma><malignancy><military population><military veteran><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><mutated in multiple advanced cancers 1 protein><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><neoplastic cell><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><p110-Alpha><pathway><pharmacologic><phase II protocol><phosphatase and tensin homologue on chromosome ten><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein ligand 1><programmed death 1><protein death-ligand 1><proto-oncogene protein RAC><proto-oncogene protein akt><rac protein kinase><recruit><related to A and C-protein><resistant><response><sle2><social role><squamous cell carcinoma of the lung><success><systemic lupus erythematosus susceptibility 2><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><thymus derived lymphocyte><translational opportunities><translational potential><treatment strategy><tumor><tumor cell metabolism><tumor growth><tumor immune microenvironment><tumor metabolism><tumor-immune system interactions><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine candidates against SARS-CoV-2><vaccine for novel coronavirus><vaccines preventing COVID><vaccines to prevent COVID><vascular><veteran population><αPD-1><αPD1>