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:
- 金额:$ 60.78万
- 依托单位:
- 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:
- 关键词:AntigensBAY 54-9085Biological MarkersBiologyCTNNB1 geneCancer ModelCancer PatientCellular Metabolic ProcessCharacteristicsCirrhosisClinicClinicalClustered Regularly Interspaced Short Palindromic RepeatsCombination immunotherapyCombined Modality TherapyDataDatabasesDeath RateDependenceDevelopmentEnterobacteria phage P1 Cre recombinaseEnvironmentExcisionFDA approvedFRAP1 geneGene ExpressionGene Expression ProfilingGenesGeneticGlutamate-Ammonia LigaseGlutamatesGlutaminaseGlutamineHepatocyteHumanImmuneImmune checkpoint inhibitorImmune responseIncidenceInjectionsInnovative TherapyKnockout MiceMLL2 geneMalignant NeoplasmsMalignant neoplasm of liverMedicalMethionine SulfoximineModelingMolecularMusMutateMutationNeoadjuvant TherapyNivolumabOncogenesOncogenicOther GeneticsPD-1 inhibitorsPathway interactionsPatientsPhenotypePre-Clinical ModelPrecision therapeuticsPredispositionPrimary carcinoma of the liver cellsProductionPublic HealthPublicationsPublishingRegulationReportingResearch ProposalsResistanceRisk FactorsRoleSDZ RADSEER ProgramSamplingSirolimusSleeping BeautySmall Interfering RNATP53 geneTailTestingThe Cancer Genome AtlasTherapeuticTransposaseTumor ImmunityUnresectableVeinsWomananti-PD-1anti-PD1 therapybeta cateninchronic liver diseaseclinically relevantcohortcombinatorialcomparative efficacydesigneffective therapygain of function mutationgenome wide association studyimmune cell infiltrateimmunogenicinducible Creinhibitorlipid nanoparticleliver transplantationloss of function mutationmTOR InhibitormTOR inhibitionmenmortalitymouse modelmutantneoplastic cellnoveloverexpressionpalliationpatient subsetspersonalized medicineprecision medicinepredicting responseprogrammed cell death protein 1promoterresponseresponse biomarkertherapeutic targettumortumor initiationtumor metabolismtumor-immune system interactionstumorigenesis
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:
- 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:
- 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:
- 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:
- 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:
- 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
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{{ truncateString('Amaia Lujambio', 18)}}的其他基金
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
- 批准号:
10224895 - 财政年份:2020
- 资助金额:
$ 60.78万 - 项目类别:
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
- 批准号:
10027558 - 财政年份:2020
- 资助金额:
$ 60.78万 - 项目类别:
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
- 批准号:
10398173 - 财政年份:2020
- 资助金额:
$ 60.78万 - 项目类别:
Tumor-intrinsic signaling pathways restrict anti-tumor immunity in hepatocellular carcinoma
肿瘤内在信号通路限制肝细胞癌的抗肿瘤免疫
- 批准号:
10177960 - 财政年份:2018
- 资助金额:
$ 60.78万 - 项目类别:
Tumor-intrinsic signaling pathways restrict anti-tumor immunity in hepatocellular carcinoma
肿瘤内在信号通路限制肝细胞癌的抗肿瘤免疫
- 批准号:
10424514 - 财政年份:2018
- 资助金额:
$ 60.78万 - 项目类别:
Tumor-intrinsic signaling pathways restrict anti-tumor immunity in hepatocellular carcinoma
肿瘤内在信号通路限制肝细胞癌的抗肿瘤免疫
- 批准号:
9577542 - 财政年份:2018
- 资助金额:
$ 60.78万 - 项目类别:
Tumor-intrinsic signaling pathways restrict anti-tumor immunity in hepatocellular carcinoma
肿瘤内在信号通路限制肝细胞癌的抗肿瘤免疫
- 批准号:
10581235 - 财政年份:2018
- 资助金额:
$ 60.78万 - 项目类别: