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，日益严重，主要风险肝细胞癌（HCC）发展的因素。 HCC发病率和死亡率正在增长美国。缺乏用于HCC的最佳医疗疗法。 FDA批准的代理非常有效。免疫检查点抑制剂（ICI），包括Nivolumab和pembrozilumab，都已批准并显示良好的响应率，但仅在HCC病例的一部分中。响应的生物标志物仍然未知。近年来，HCC GWAS研究发生了一场革命，以识别分子驱动因素。突变在CTNNB1中，在Wnt途径中激活B-catenin，并在高达37％的HCC中看到。但是，B-连环蛋白激活一个人不会导致HCC。对2个大型HCC队列（TCGA和法语）的分析显示CTNNB1突变与MET，MYC，TERT，NFE2L2，MLL2，ARID2和APOB的变化相同。过表达/激活在〜11％的HCC中，可以看到与CTNNB1突变一起遇到的。这些基因在子集中的共表达使用睡美人转座子/转座酶（SB）和流体动力尾静脉注射（HTVI）LED的肝细胞在小鼠（HMET-B-catenin模型）中以6周的速度到HCC。基因表达分析证实了70％的相似性在HMET-B-catenin模型和HCC患者子集之间具有MET激活和CTNNB1突变。在AIM 1中，我们将使用SB/CRISPR和HTVI生成和表征鼠标模型，以表达突变体CTNNB1和其他经常在人类HCC子集的基因，包括MYC，TERT，NFE2L2，MLL2，ARID2，＆ apob。我们已经显示了Met-B-catenin，myc-b-catenin，tert-b-catenin＆nfe2l2-b-的HCC开发 Catenin，而其他人则正在进行。小鼠模型与人HCC之间基因表达的比较子集将验证这些模型的相关性，以证明更全面的蜂窝和分子是合理的创新疗法的特征。我们还将测试所有突变CTNNB1小鼠模型的依赖性 B-catenin使用含有CTNNB1-SIRNA（CTNNB1-LNP）的脂质纳米颗粒（LNP）抑制B- 正如我们对Kras-B-catenin（类似于HMET-B-catenin）模型所表明的那样，Catenin和评估反应。在AIM 2中，我们将专注于突变体-CTNNB1 HCC中的B-连环蛋白 - 谷氨酰胺合成酶（GS） - 谷氨酰胺-MTORC1轴，最近我们发现并报告了（细胞代谢的出版物）。所有突变体-CTNNB1驱动的HCC模型所有共发生将测试对MTORC1抑制剂（如Everolimus和RM-006）的响应（新型通过固定的HCC中的GS或通过使用，独家MTORC1抑制剂和上游GS上游GS 不可逆的GS抑制剂L-甲硫代硫胺（MSO）和谷氨酰胺酶抑制剂CB-839 GS生成谷氨酰胺的谷氨酸的产生。在AIM 3中，我们将调查如何制作B- 我们证明的Catenin Active HCC对ICI具有抵抗力（癌症发现），对ICIS敏感通过使用组合疗法。使用免疫原性myc-lucos-Mutant-b-catenin HCC模型，即对PD-1抑制剂的抗性，我们将通过CTNNB1-LNP，MTORC1测试伴随B-catenin抑制的作用通过Everolimus或GS抑制MSO抑制作用，作为对PD-1抑制剂的敏化剂。因此，总的来说，我们的提案将利用突变体B-catenin作为一个临床相关且经过验证的临床前模型癌基因合作并证明突变体B-catenin在调节肿瘤代谢和免疫中的作用微环境。因此，我们的研究的完成将为靶向B-catenin提供著名的理由通过创新疗法的HCC患者子集，并最终为个性化医学铺平了道路。

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

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

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

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