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Targeting tumor metabolism and immune environment via beta-catenin: Towards precision medicine in HCC

通过 β-连环蛋白靶向肿瘤代谢和免疫环境：走向 HCC 精准医疗

基本信息

批准号：
10398173
负责人：
Amaia Lujambio
金额：
$ 60.78万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10398173
关键词：
Antigens BAY 54-9085 Biological Markers Biology CTNNB1 gene Cancer Model Cancer Patient Cells Cellular Metabolic Process Characteristics Cirrhosis Clinic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Combination immunotherapy Combined Modality Therapy Data Databases Death Rate Dependence Development Enterobacteria phage P1 Cre recombinase Environment Excision FDA approved FRAP1 gene Gene Expression Gene Expression Profiling Genes Genetic Glutamate-Ammonia Ligase Glutamates Glutaminase Glutamine Hepatocyte Human Immune Immune checkpoint inhibitor Immune response Incidence Infiltration Injections Innovative Therapy Knockout Mice Lead MLL2 gene Malignant Neoplasms Malignant neoplasm of liver Medical Methionine Sulfoximine Modeling Molecular Mus Mutate Mutation Neoadjuvant Therapy Nivolumab Oncogenes Oncogenic Other Genetics PD-1 inhibitors Pathway interactions Patients Phenotype Pre-Clinical Model Precision therapeutics Predisposition Primary carcinoma of the liver cells Production Public Health Publications Publishing Regulation Reporting Research Proposals Resistance Risk Factors Role SDZ RAD SEER Program Sampling Sirolimus Sleeping Beauty Small Interfering RNA TP53 gene Tail Testing The Cancer Genome Atlas Therapeutic Transposase Tumor Immunity Unresectable Veins Woman anti-PD-1 anti-PD1 therapy base beta catenin chronic liver disease clinically relevant cohort combinatorial comparative efficacy design effective therapy gain of function mutation genome wide association study immunogenic inhibitor lipid nanoparticle liver transplantation loss of function mutation mTOR Inhibitor mTOR inhibition men mortality mouse model mutant neoplastic cell novel overexpression palliation patient subsets personalized medicine precision medicine predicting response programmed cell death protein 1 promoter response response biomarker therapeutic target tumor tumor initiation tumor metabolism tumor-immune system interactions tumorigenesis

项目摘要

Chronic liver disease and its common sequela cirrhosis, are growing public health concerns, and major risk factors for the development of hepatocellular cancer (HCC). HCC incidence and mortality is growing in the USA. Optimal medical therapies for HCC are lacking. FDA approved agents are modestly effective. Immune checkpoint inhibitors (ICIs) including PD-1 inhibitors Nivolumab and Pembrozilumab, have been both approved and show good response rates but only in a subset of HCC cases. Biomarkers of response remain unknown. Recent years have seen a revolution in HCC GWAS studies to identify molecular drivers. Mutations in CTNNB1 activate b-catenin in the Wnt pathway & seen in up to 37% of HCCs. However, b-catenin activation alone does not lead to HCC. Analysis of 2 large HCC cohorts (TCGA & French) revealed CTNNB1 mutations to co-occur with alterations in MET, MYC, TERT, NFE2L2, MLL2, ARID2 & APOB. Overexpression/activation of Met along with CTNNB1 mutations is seen in ~11% of HCCs. Coexpression of these genes in a subset of hepatocytes using sleeping beauty transposon/transposase (SB) & hydrodynamic tail vein injection (HTVI) led to HCC by 6 weeks in mice (hMet-b-catenin model). Gene expression analysis confirmed 70% similarity between hMet-b-catenin model and HCC patient subset with Met activation & CTNNB1 mutations. In aim 1, we will generate and characterize mouse models using SB/Crispr and HTVI to co-express mutant CTNNB1 and other genes frequently co-altered in subsets of human HCC including MYC, TERT, NFE2L2, MLL2, ARID2, & APOB. We already show HCC development in Met-b-catenin, MYC-b-catenin, TERT-b-catenin & NFE2L2-b- catenin, while others are ongoing. Comparison of gene expression between mouse models and human HCC subsets will validate the relevance of these models justifying a more comprehensive cellular & molecular characterization for innovative therapies. We will also test dependence of all mutant CTNNB1-mouse models to b-catenin by using of lipid nanoparticles (LNP) containing CTNNB1-siRNA (CTNNB1-LNP) to suppress b- catenin and assess response as we have shown for Kras-b-catenin (akin to hMet-b-catenin) model. In aim 2, we will focus on b-catenin-glutamine synthetase (GS)-glutamine-mTORC1 axis in mutant-CTNNB1 HCC, recently discovered and reported by us (Publication in Cell Metabolism). All mutant-CTNNB1 driven HCC models with all co-occurrences will be tested for response to mTORC1 inhibitors like Everolimus and RM-006 (novel exclusive mTORC1 inhibitor) and to upstream GS via genetic deletion of GS in established HCCs or via use of irreversible GS inhibitor L-methionine sulfoximine (MSO) and glutaminase inhibitor CB-839 that hampers production of glutamate, a substrate for GS to generate glutamine. In aim 3, we will investigate how to make b- catenin-active HCCs shown by us to be resistant to ICIs (publication in Cancer Discovery), sensitive to ICIs through use of combination therapy. Using an immunogenic Myc-lucOS-mutant-b-catenin HCC model, that is resistant to PD-1 inhibitor, we will test role of concomitant b-catenin suppression via CTNNB1-LNP, mTORC1 inhibition via Everolimus or GS inhibition via MSO, as sensitizing agents to PD-1 inhibitor. Thus overall, our proposal will develop clinically relevant and validated preclinical models utilizing mutant b-catenin as one cooperating oncogene and demonstrate role of mutant b-catenin in regulating tumor metabolism and immune microenvironment. Completion of ours study will thus provide justification for targeting b-catenin in a notable subset of HCC patients through innovative therapies and eventually pave the way for personalized medicine.

慢性肝病及其常见的后遗症肝硬化，是日益受到关注的公共卫生问题和主要风险