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Principal Investigator: Amaia Lujambio
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $367,259
Funding agency: National Cancer Institute
PROJECT SUMMARY (from parent application)
Hepatocellular carcinoma (HCC) represents a major health problem, causing more than 700,000 deaths
annually worldwide. Although HCC treatment has greatly improved over the last decades, most HCC patients
diagnosed at advanced stages are ineligible for curative ablative therapies such as liver resection or
transplantation. Until recently, the only FDA-approved therapies for such patients were sorafenib and
regorafenib, used as first-line and second-line therapy, respectively. Unfortunately, these two closely related
multikinase inhibitors provide limited survival benefits. In September 2017, nivolumab, a PD-1 (programmed
cell death 1) immune checkpoint inhibitor, was granted accelerated approval by the FDA for HCC treatment in
second line, after the promising results obtained in a phase II clinical trial (NCT01658878). Despite some HCC
patients show unprecedented responses with nivolumab, not all patients respond, indicating the existence of
mechanisms that drive resistance to anti-PD-1 therapy and highlighting the urgent need to identify biomarkers
for optimal patient selection and strategies to overcome resistance. Studies in other tumor types demonstrate
that different tumor-intrinsic oncogenic pathways, such as PI3K or WNT/β-catenin, promote immune escape
and confer resistance to anti-PD-1 therapy but also inform patient stratification and strategies to overcome
resistance. Our central hypothesis is that specific oncogenic signaling pathways activated in HCC amplify the
mechanisms of immune evasion and thereby impair the response to anti-PD-1 therapy. By using a novel
mouse model of HCC immune surveillance that we have recently created, we have recently demonstrated that
CTNNB1 (β-catenin), PTEN, and KMT2C (MLL3), three genes frequently altered in human HCC, are involved
in immune escape, demonstrating the feasibility of the project. Moreover, CTNNB1 activation confers
resistance to anti-PD-1 blockade and could potentially serve as a biomarker for patient exclusion. Here, by
combining this novel mouse model, human HCC samples, and transcriptional and immune profilings, we will
establish the signaling pathways that promote immune escape in HCC, the underlying mechanisms of immune
escape, and their effects on response to anti-PD-1 therapy.
Terms: <1-Phosphatidylinositol 3-Kinase><Abscission><Acceleration><Address><Affect><Anti-Oncogenes><Antioncogene Protein p53><Antioncogenes><Apoptosis Regulator BAK><Applications Grants><Avian Myelocytomatosis Viral Oncogene Homolog><BAY 54-9085><BCL2-Antagonist/Killer 1><Bcl-2 Homologous Antagonist/Killer><Beta Cadherin-Associated Protein><Beta-1 Catenin><Biological Markers><CRISPR><CRISPR/Cas system><CTNNB><CTNNB1><CTNNB1 gene><CUL-2><Cancer Genes><Cancer Suppressor Genes><Cancer-Promoting Gene><Cell Death Inhibitor 1><Cellular Tumor Antigen P53><Cessation of life><Checkpoint inhibitor><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats><Death><Diagnosis><Emerogenes><Excision><Exclusion><Extirpation><FDA approved><GEM model><GEMM model><Gene Transcription><Genes><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genetically Engineered Mouse><Grant><Grant Proposals><Health><Hepatic Cancer><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocarcinoma><Hepatocarcinoma model><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatocyte><Hepatoma><Human><Immune><Immune Evasion><Immune Surveillance><Immune checkpoint inhibitor><Immune mediated therapy><Immune response><Immune system><Immunes><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunological response><Immunologically Directed Therapy><Immunosurveillance><Immunotherapy><Impairment><Keytruda><Liver><Liver Cells><Liver Cells Carcinoma><MMAC1><MMAC1 protein><MYC gene><Malignant Cell><Malignant neoplasm of liver><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Mutated in Multiple Advanced Cancers 1><Mutation><Nivolumab><Onco-Suppressor Genes><Oncogenes><Oncogenes-Tumor Suppressors><Oncogenic><Oncoprotein p53><Opdivo><P53><PD 1><PD-1><PD-1 antibody therapy><PD-1 therapy><PD1><PD1 antibody therapy><PD1 based treatment><PHTS gene><PHTS protein><PI-3 Kinase><PI3-Kinase><PI3CG><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><PRO2286><PTEN><PTEN gene><PTEN protein><PTEN1><Parents><Pathway interactions><Patient Selection><Patients><Phase><Phase 2 Clinical Trials><Phase II Clinical Trials><Phenotype><Phosphatase and Tensin Homolog><Phosphatase and Tensin Homolog Deleted on Chromosome 10><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Phosphoprotein P53><Phosphoprotein pp53><Primary carcinoma of the liver cells><Protein TP53><PtdIns 3-Kinase><RNA Expression><Recessive Oncogenes><Refractory><Removal><Resistance><Sampling><Signal Pathway><Sorafenib><Surgical Removal><T cell infiltration><TP53><TP53 gene><TRP53><Tail><Testing><Transcription><Transforming Genes><Transplantation><Tumor Antigens><Tumor Cell><Tumor Escape><Tumor Immune Escape><Tumor Immunity><Tumor Protein p53><Tumor Protein p53 Gene><Tumor Suppressing Genes><Tumor Suppressor Genes><Tumor-Associated Antigen><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><Veins><aPD-1><aPD-1 therapy><aPD-1 treatment><aPD1><aPD1 therapy><aPD1 treatment><anti programmed cell death 1><anti-PD-1><anti-PD-1 therapy><anti-PD-1 treatment><anti-PD1><anti-PD1 therapy><anti-PD1 treatment><anti-cancer immunotherapy><anti-programmed cell death 1 therapy><anti-programmed cell death protein 1><anti-programmed cell death protein 1 therapy><anti-tumor immunity><antiPD-1><antiPD1><anticancer immunotherapy><antitumor immunity><bak protein><bcl-2 homologous antagonist-killer protein><beta catenin><bio-markers><biologic marker><biomarker><biomarker identification><cancer antigens><cancer cell><cancer evasion><cancer immune escape><cancer immune evasion><cancer immunity><cancer immunotherapy><design><designing><experiment><experimental research><experimental study><experiments><genetic element><genetically engineered mouse model><genetically engineered murine model><genome mutation><hepatic body system><hepatic organ system><hepatocellular carcinoma cancer model><hepatocellular carcinoma model><host response><human disease><identification of biomarkers><identification of new biomarkers><immune check point inhibitor><immune evasive><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunogenicity><immunoresponse><immunotherapy for cancer><immunotherapy of cancer><improved><inhibitor><liver cancer><liver cancer model><liver carcinoma><liver malignancy><malignant liver tumor><marker identification><mouse model><murine model><mutated in multiple advanced cancers 1 protein><myc Oncogenes><neoplastic cell><novel><oncosuppressor gene><overexpress><overexpression><p53 Antigen><p53 Genes><p53 Tumor Suppressor><parent><parent grant><pathway><patient biomarkers><patient stratification><pembrolizumab><phase II protocol><phosphatase and tensin homologue on chromosome ten><programmed cell death 1><programmed cell death protein 1><programmed cell death protein 1 therapy><programmed death 1><protein p53><resection><resistant><response><sle2><stratified patient><systemic lupus erythematosus susceptibility 2><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcriptomics><transplant><tumor><tumor evasion><tumor immune evasion><tumor-specific antigen><vector><αPD-1><αPD1><β-catenin>