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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：
ROGER S LO
金额：
$ 37.05万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
https://reporter.nih.gov/project-details/9912727
关键词：
ATAC-seq Address Antibodies Antigen Presentation Automobile Driving BRAF gene CD8-Positive T-Lymphocytes Catalogs Cell Compartmentation Cell Line ChIP-seq Clinical DNA Methylation Data Dependence Development Disease Progression Enhancers Epigenetic Process Evolution Experimental Models Foundations Future Genes Genome Genomics Growth Factor Human Immune Immunocompetent Immunologic Memory Immunologics Immunotherapy In Vitro Inflammation Life Link MAP Kinase Gene MEKs Melanoma Cell Mitogen-Activated Protein Kinase Inhibitor Modeling Mus Mutation PD-L1 blockade PTPRC gene Pathway interactions Patients Phenotype Process Proto-Oncogene Proteins c-akt Public Health Publishing RNA analysis Recurrence Resistance Resistance development Signal Pathway Signal Transduction Sustainable Development T-Cell Development T-Lymphocyte T-cell inflamed Testing Time Tissue Sample Transforming Growth Factor beta Translating Translations Tumor Tissue VEGFA gene Work Xenograft procedure addiction anti-PD-1 anti-PD-L1 anti-PD1 therapy anticancer research base bone morphogenetic protein receptors cancer therapy combinatorial comparative epigenome epigenomics exhaustion immune checkpoint immune resistance in vivo inhibitor/antagonist insight melanoma member mutant neoplastic cell neutralizing antibody next generation non-genomic pre-clinical programmed cell death ligand 1 promoter resistance mechanism response restoration single-cell RNA sequencing small molecular inhibitor therapy resistant transcription factor transcriptome transcriptome sequencing transcriptomics tumor tumor microenvironment tumor-immune system interactions unpublished works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