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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：迈向 HCC 精准医疗

基本信息

批准号：
10605197
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/10605197
关键词：
Antigens BAY 54-9085 Biological Markers Biology CTNNB1 gene Cancer Model Cancer Patient 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 Injections Innovative Therapy Knockout Mice 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 beta catenin chronic liver disease clinically relevant cohort combinatorial comparative efficacy design effective therapy gain of function mutation genome wide association study immune cell infiltrate immunogenic inducible Cre 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，是日益受到公众关注的健康问题，也是主要的风险肝细胞癌（HCC）的发展因素。HCC的发病率和死亡率正在增长， USA.目前缺乏针对HCC的最佳药物治疗。FDA批准的药物是适度有效的。免疫检查点抑制剂（ICI），包括PD-1抑制剂纳武单抗和派姆单抗，获得批准并显示良好的反应率，但仅在HCC病例的子集中。反应的生物标志物仍然存在未知近年来，HCC GWAS研究发生了革命性的变化，以确定分子驱动因素。突变 CTNNB 1激活Wnt通路中的β-连环蛋白&见于高达37%的HCC。然而，b-连环蛋白激活但这并不会导致HCC。2个大型HCC队列（TCGA和French）的分析显示CTNNB 1突变，与MET、MYC、TERT、NFE 2L 2、MLL 2、ARID 2和APOB中的改变共同发生。过表达/激活 Met沿着CTNNB 1突变见于约11%的HCC。这些基因在一个亚群中的共表达使用睡美人转座子/转座酶（SB）和水动力尾静脉注射（HTVI）的肝细胞在小鼠中，通过6周的时间（hMet-b-连环蛋白模型），基因表达分析证实了70%的相似性 hMet-b-catenin模型和具有Met激活和CTNNB 1突变的HCC患者亚组之间的差异。在目标1中，我们将使用SB/Crispr和HTVI共表达突变CTNNB 1和在人HCC的亚群中经常共改变的其他基因包括MYC、TERT、NFE 2L 2、MLL 2、ARID 2和 APOB。我们已经在Met-B-连环蛋白、MYC-B-连环蛋白、TERT-B-连环蛋白和NFE 2L 2-B-连环蛋白中显示了HCC的发展。而其他的则在进行中。小鼠肝癌模型与人肝癌基因表达的比较子集将验证这些模型的相关性，从而证明更全面的细胞和分子生物学模型的合理性。创新疗法的特征。我们还将测试所有突变CTNNB 1-小鼠模型对通过使用含有CTNNB 1-siRNA的脂质纳米颗粒（LNP）（CTNNB 1-LNP）来抑制B-连环蛋白，如我们已经针对Kras-b-连环蛋白（类似于hMet-b-连环蛋白）模型所示，在目标2中，我们最近，我将重点关注mCTNNB 1肝癌中的b-连环蛋白-谷氨酰胺合成酶（GS）-谷氨酰胺-mTORC 1轴，发现和报告由我们（出版细胞代谢）。所有具有以下特征的MUSC-CTNNB 1驱动的HCC模型将检测所有共同发生的事件对mTORC 1抑制剂如依维莫司和RM-006（新型特异性mTORC 1抑制剂）和通过在已建立的HCC中遗传缺失GS或通过使用不可逆GS抑制剂L-甲硫氨酸亚砜亚胺（MSO）和转氨酶抑制剂CB-839，谷氨酸盐的产生，谷氨酸盐是GS产生谷氨酰胺的底物。在目标3中，我们将研究如何使B- 我们显示连环蛋白活性HCC对ICI具有抗性（发表于Cancer Discovery），对ICI敏感通过使用联合疗法。使用免疫原性Myc-lucOS-mucos-b-catenin HCC模型，即对PD-1抑制剂耐药，我们将通过CTNNB 1-LNP、mTORC 1检测伴随的b-连环蛋白抑制作用通过依维莫司的抑制或通过MSO的GS抑制，作为PD-1抑制剂的增敏剂。总体而言，我们一项提案将开发临床相关的和验证的临床前模型，利用突变的b-连环蛋白作为一种协同癌基因并证明突变b-连环蛋白在调节肿瘤代谢和免疫中的作用微环境因此，我们研究的完成将为靶向b-连环蛋白提供理由，通过创新的治疗方法为HCC患者的亚群提供治疗，并最终为个性化医疗铺平道路。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dual β-Catenin and γ-Catenin Loss in Hepatocytes Impacts Their Polarity through Altered Transforming Growth Factor-β and Hepatocyte Nuclear Factor 4α Signaling.

肝细胞中双 β-连环蛋白和 γ-连环蛋白丢失通过改变转化生长因子-β 和肝细胞核因子 4α 信号传导影响其极性。

DOI：
10.1016/j.ajpath.2021.02.008
发表时间：
2021
期刊：
The American journal of pathology
影响因子：
0
作者：
Pradhan-Sundd,Tirthadipa;Liu,Silvia;Singh,Sucha;Poddar,Minakshi;Ko,Sungjin;Bell,Aaron;Franks,Jonathan;Huck,Ian;Stolz,Donna;Apte,Udayan;Ranganathan,Sarangarajan;Nejak-Bowen,Kari;Monga,SatdarshanP
通讯作者：
Monga,SatdarshanP

Tumor-Intrinsic Mechanisms Regulating Immune Exclusion in Liver Cancers.

DOI：
10.3389/fimmu.2021.642958
发表时间：
2021
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Lindblad KE;Ruiz de Galarreta M;Lujambio A
通讯作者：
Lujambio A

β-Catenin-NF-κB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reaction.

胆管细胞中的β-catenin-NF-κB-CFTR相互作用调节导管反应过程中的炎症和纤维化。

DOI：
10.7554/elife.71310
发表时间：
2021-10-05
期刊：
eLife
影响因子：
7.7
作者：
Hu S;Russell JO;Liu S;Cao C;McGaughey J;Rai R;Kosar K;Tao J;Hurley E;Poddar M;Singh S;Bell A;Shin D;Raeman R;Singhi AD;Nejak-Bowen K;Ko S;Monga SP
通讯作者：
Monga SP

Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b.

DOI：
10.1016/j.xcrm.2022.100754
发表时间：
2022-10-18
期刊：
CELL REPORTS MEDICINE
影响因子：
14.3
作者：
Hu, Shikai;Liu, Silvia;Bian, Yu;Poddar, Minakshi;Singh, Sucha;Cao, Catherine;McGaughey, Jackson;Bell, Aaron;Blazer, Levi L.;Adams, Jarret J.;Sidhu, Sachdev S.;Angers, Stephane;Monga, Satdarshan P.
通讯作者：
Monga, Satdarshan P.

Hepatocyte β-catenin loss is compensated by Insulin-mTORC1 activation to promote liver regeneration.

肝细胞β-连环蛋白损失通过胰岛素-mTORC1 激活来补偿，以促进肝再生。

DOI：
10.1002/hep.32680
发表时间：
2023
期刊：
Hepatology (Baltimore, Md.)
影响因子：
0
作者：
Hu,Shikai;Cao,Catherine;Poddar,Minakshi;Delgado,Evan;Singh,Sucha;Singh-Varma,Anya;Stolz,DonnaBeer;Bell,Aaron;Monga,SatdarshanP
通讯作者：
Monga,SatdarshanP