Combinatorial Targeting of Epigenomic and Microenvironmental Pathways to Suppress MAPK Inhibitor Resistance in Melanoma
表观基因组和微环境途径的组合靶向抑制黑色素瘤中 MAPK 抑制剂耐药性
基本信息
- 批准号:9912727
- 负责人:
- 金额:$ 37.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-08-07 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:ATAC-seqAddressAntibodiesAntigen PresentationAutomobile DrivingBRAF geneCD8-Positive T-LymphocytesCatalogsCell CompartmentationCell LineChIP-seqClinicalDNA MethylationDataDependenceDevelopmentDisease ProgressionEnhancersEpigenetic ProcessEvolutionExperimental ModelsFoundationsFutureGenesGenomeGenomicsGrowth FactorHumanImmuneImmunocompetentImmunologic MemoryImmunologicsImmunotherapyIn VitroInflammationLifeLinkMAP Kinase GeneMEKsMelanoma CellMitogen-Activated Protein Kinase InhibitorModelingMusMutationPD-L1 blockadePTPRC genePathway interactionsPatientsPhenotypeProcessProto-Oncogene Proteins c-aktPublic HealthPublishingRNA analysisRecurrenceResistanceResistance developmentSignal PathwaySignal TransductionSustainable DevelopmentT-Cell DevelopmentT-LymphocyteT-cell inflamedTestingTimeTissue SampleTransforming Growth Factor betaTranslatingTranslationsTumor TissueVEGFA geneWorkXenograft procedureaddictionanti-PD-1anti-PD-L1anti-PD1 therapyanticancer researchbasebone morphogenetic protein receptorscancer therapycombinatorialcomparativeepigenomeepigenomicsexhaustionimmune checkpointimmune resistancein vivoinhibitor/antagonistinsightmelanomamembermutantneoplastic cellneutralizing antibodynext generationnon-genomicpre-clinicalprogrammed cell death ligand 1promoterresistance mechanismresponserestorationsingle-cell RNA sequencingsmall molecular inhibitortherapy resistanttranscription factortranscriptometranscriptome sequencingtranscriptomicstumortumor microenvironmenttumor-immune system interactionsunpublished works
项目摘要
ABSTRACT
Mutation-targeted small molecular inhibitors and immune checkpoint antibodies have extended the quality and
quantity of life for patients with advanced MUTBRAF melanoma. Development of combinations based on these
foundational therapies should yield further survival benefits in the near future. The combo of BRAF and MEK
inhibitors specifically suppresses a form of resistance driven mainly by genetic alterations that result in MAPK-
reactivation and restoration of MAPK-addiction. However, this clinically validated approach to suppress BRAF
inhibitor resistance does not address epigenomic and immunologic alterations that drive resistance via MAPK-
redundant and CD8 T-cell-depleted tumor states. We propose to uncover combinatorial targets in advanced
V600BRAF mutant melanoma by understanding MAPK inhibitor-induced epigenomic and immune-suppressive
mechanisms and their interplay. We hypothesize that MAPK inhibitor-induced tumor cell-intrinsic and extrinsic
adaptations, which have been linked to innate anti-PD-1 resistance, converge on the elaboration and actions of
TGFβ, BMP, or VEGFA in the tumor immune microenvironment.
The Lo Lab has a track record of integrating analysis of clinical and experimental resistance evolution to derive
translatable preclinical strategies to suppress resistance. We propose (Aim 1) to generate a landscape
perspective of epigenome-directed tumor cell-intrinsic resistance evolution by comparative analysis of human
melanoma cell lines, patient-derived xenografts and immune-competent murine melanoma models. This analysis
seeks to identify master transcriptional factors regulating phenotypic transitions to provide insights into
resistance-regulatory growth factors and signaling pathways. In Aim 2, we will test the hypothesis that MAPK
inhibitors induce adaptive epigenomic and immune-suppressive processes via elaboration of specific TGFβs or
BMPs. The action of these factors on the tumor cells and the tumor microenvironment will be analyzed,
respectively, by characterization of cis-regulatory enhancer or super-enhancer modules involving TGFβ/BMP
receptor-regulated SMADs and by single-cell RNA-seq of dissociated tumors. In Aim 3, we will evaluate the
efficacy and mechanisms of blocking TGFβ, BMP, or VEGFA on top of the MAPKi+aPD-L1 foundation and
dissect the influence of the most efficacious combination on single T-cell clonotypes and epigenetic states of
activation or exhaustion. Together, these studies will advance translation of our understanding of multi-faceted
resistance mechanisms into next-generation combinatorial therapies for advanced melanoma.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ROGER S LO其他文献
ROGER S LO的其他文献
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{{ truncateString('ROGER S LO', 18)}}的其他基金
Core 1: Mouse Model and Tissue Biobank Core
核心 1:小鼠模型和组织生物库核心
- 批准号:
10526106 - 财政年份:2022
- 资助金额:
$ 37.05万 - 项目类别:
Core 1: Mouse Model and Tissue Biobank Core
核心 1:小鼠模型和组织生物库核心
- 批准号:
10708931 - 财政年份:2022
- 资助金额:
$ 37.05万 - 项目类别:
Understanding PD-L1/L2 protein regulation, detection and signaling to predict melanoma therapeutic sensitivity
了解 PD-L1/L2 蛋白调控、检测和信号传导以预测黑色素瘤治疗敏感性
- 批准号:
10358524 - 财政年份:2021
- 资助金额:
$ 37.05万 - 项目类别:
Project 1: Strategies to enhance MEK inhibitor efficacy in MUTNRAS melanoma
项目 1:增强 MEK 抑制剂对 MUTNRAS 黑色素瘤疗效的策略
- 批准号:
10261396 - 财政年份:2020
- 资助金额:
$ 37.05万 - 项目类别:
Project 1: Strategies to enhance MEK inhibitor efficacy in MUTNRAS melanoma
项目 1:增强 MEK 抑制剂对 MUTNRAS 黑色素瘤疗效的策略
- 批准号:
10443859 - 财政年份:2020
- 资助金额:
$ 37.05万 - 项目类别:
Project 1: Strategies to enhance MEK inhibitor efficacy in MUTNRAS melanoma
项目 1:增强 MEK 抑制剂对 MUTNRAS 黑色素瘤疗效的策略
- 批准号:
10025136 - 财政年份:2020
- 资助金额:
$ 37.05万 - 项目类别:
Combinatorial Targeting of Epigenomic and Microenvironmental Pathways to Suppress MAPK Inhibitor Resistance in Melanoma
表观基因组和微环境途径的组合靶向抑制黑色素瘤中 MAPK 抑制剂耐药性
- 批准号:
10439777 - 财政年份:2013
- 资助金额:
$ 37.05万 - 项目类别:
Combinatorial Targeting of Epigenomic and Microenvironmental Pathways to Suppress MAPK Inhibitor Resistance in Melanoma
表观基因组和微环境途径的组合靶向抑制黑色素瘤中 MAPK 抑制剂耐药性
- 批准号:
10189526 - 财政年份:2013
- 资助金额:
$ 37.05万 - 项目类别:
Overcoming acute, adaptive BRAF inhibitor resistance in melanoma
克服黑色素瘤中急性、适应性 BRAF 抑制剂耐药性
- 批准号:
8595186 - 财政年份:2013
- 资助金额:
$ 37.05万 - 项目类别:
Overcoming acute, adaptive BRAF inhibitor resistance in melanoma
克服黑色素瘤中急性、适应性 BRAF 抑制剂耐药性
- 批准号:
9283342 - 财政年份:2013
- 资助金额:
$ 37.05万 - 项目类别:
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