Targetable epigenetic and transcriptional mechanisms in melanoma that shape the microenvironment

黑色素瘤中塑造微环境的靶向表观遗传和转录机制

• 批准号: 9792731
• 负责人: DAVID E FISHER
• 金额: $ 151.67万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-12 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9792731
• 关键词: ATAC-seq; Advisory Committees; Affect; Animal Model; Behavior; Bioinformatics; Biological Markers; Biometry; Biopsy; Budgets; Cell Line; Cell Nucleus; Cellular Immunity; ChIP-seq; Chromatin; Chromatin Remodeling Factor; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; Committee Members; Communication; Complex; Computer Analysis; Computer Simulation; Data; Development; Disease; Disease Progression; Drug resistance; ETV1 gene; Epigenetic Process; Exhibits; Expenditure; Family member; Funding; G9a histone methyltransferase; Gene Expression Regulation; Genes; Genetic; Genetic Screening; Genetic Transcription; Genomics; Goals; Human; Image Analysis; Immune; Immunofluorescence Immunologic; Immunosuppressive Agents; Immunotherapy; In Vitro; Infrastructure; Logistics; MAP Kinase Gene; Malignant Neoplasms; Mediating; Mediator of activation protein; Melanoma Cell; Metastatic Melanoma; Mitogen-Activated Protein Kinases; Modeling; Multiplexed Ion Beam Imaging; Oncogenes; Outcome; Outcome Study; Pathway interactions; Patients; Pre-Clinical Model; Preparation; Program Research Project Grants; Progress Reports; Proteins; Research; Research Personnel; Research Project Grants; Resistance; Resource Sharing; Role; SWI/SNF Family Complex; Sampling; Shapes; Signal Transduction; Specimen; Systemic Therapy; T-Lymphocyte; Testing; Therapeutic; Validation; Zebrafish; anti-tumor immune response; cancer cell; cancer therapy; cell motility; checkpoint therapy; chemical genetics; chromatin remodeling; clinical development; data management; data sharing; epigenetic regulation; epigenomics; experience; gain of function mutation; genetic regulatory protein; immune checkpoint blockade; improved; inhibitor/antagonist; insight; loss of function mutation; meetings; melanoma; member; mouse model; mutant; novel; programs; resistance mechanism; response; response biomarker; small molecule inhibitor; success; targeted treatment; therapeutic target; therapy resistant; transcription factor; transcriptome; transcriptome sequencing; tumor; tumor microenvironment; tumorigenesis

Overall Summary The overall goal of this proposal for renewal of P01 CA163222 is to further improve responses of metastatic melanoma to MAP kinase pathway-targeted and immune checkpoint therapies, by targeting aberrant tumor- intrinsic epigenetic regulation of gene expression, with a focus on enhancing the tumor immune microenvironment. While those revolutionary therapies have provided major improvements in melanoma outcomes, and advances in the past five years by us (in this Program Project) and others have substantially improved the outlook for overcoming therapeutic resistance, the majority of patients still experience eventual disease progression and fatality. Even with our significant successes in identifying resistance mechanisms and novel potential therapeutic strategies, there remains an urgent need to discover additional mechanisms and potential targets in acquired and intrinsic resistance to targeted and immune therapies for melanoma. Our current approach incorporates mechanistic insights uncovered by investigators under this Program Project Grant (PPG) and by other groups, namely the importance of genetic aberrations in epigenetic regulatory machinery in resistance to therapy, at least partially by reshaping the tumor immune microenvironment, and as potential targets for overcoming resistance. The three research projects in this proposal describe partially uncovered mechanisms by which different epigenetic and transcriptional regulators drive melanoma resistance to therapy and might be targeted therapeutically. These regulators include genomic copy number gains and newly described gain-of-function mutations in the histone methyltransferase G9a, relocalization in chromatin of the ETS transcription factor family member ETV1, and loss-of-function mutations in PBAF components of the SWI/SNF chromatin remodeling complexes. These regulators will be investigated in vitro and in multiple preclinical models in order to gain deeper understandings of their resistance mechanisms, particularly their effects on the anti-tumor immune response, as well as to identify biomarkers of response to and assess the feasibility of therapeutic strategies targeting them. Identification of resistance mediators and biomarkers of response will be corroborated in human pre- and on-treatment melanoma biopsies, which are readily available through our robust, independently funded Melanoma Patient Biopsy Program developed, in part, with funding from this P01. Complex integration and analysis of complementary epigenetic and transcriptional data (RNA- seq, ATAC-seq, and ChIP-seq) generated in all three projects will be performed by a Shared Resources Core using state-of-the-art computational analysis and validation models. The expected outcome of these studies is a more complete understanding of the mechanisms through which epigenetic and transcriptional regulators drive resistance to targeted and immune cancer therapies, setting the stage for development of clinical trials aimed at providing complete and durable responses to therapies for advanced melanoma and other cancers.

总体摘要 这项更新P01 CA163222的提案的总体目标是进一步改善转移瘤的反应 黑色素瘤通过靶向异常肿瘤来映射激酶通路靶向和免疫检查点治疗 基因表达的内在表观遗传调节，重点是增强肿瘤免疫 微环境。虽然这些革命性的疗法在黑色素瘤方面取得了重大进展 我们(在本计划项目中)和其他人在过去五年中取得的成果和进展 改善了克服治疗阻力的前景，大多数患者最终仍会经历 疾病进展和死亡率。即使我们在识别抗性机制和 新的潜在治疗策略，仍然迫切需要发现更多的机制和 针对黑色素瘤的靶向治疗和免疫治疗的获得性和内在抵抗的潜在靶点。我们的 目前的方法结合了调查人员在该计划项目下发现的机械性见解 Grant(PPG)和其他小组的研究，即遗传异常在表观遗传调控中的重要性 抵抗治疗的机制，至少部分是通过重塑肿瘤免疫微环境，以及AS 克服抗药性的潜在目标。该提案中的三个研究项目部分描述了 不同表观遗传和转录调控因子驱动黑色素瘤耐药机制的研究 接受治疗，并可能成为治疗的靶点。这些调节因素包括基因组拷贝数增加和 组蛋白甲基转移酶G9a的新功能获得突变，染色质中的重新定位 ETS转录因子家族成员ETV1与猪PBAF组分功能丧失突变 SWI/SNF染色质重塑复合体。这些调节剂将在体外和多个 临床前模型，以便更深入地了解它们的耐药机制，特别是它们的 对抗肿瘤免疫反应的影响，以及识别和评估对 针对他们的治疗策略的可行性。棉铃虫抗性介体和生物标志物的鉴定 反应将在治疗前和治疗中的人类黑色素瘤活组织检查中得到证实，这些活组织检查很容易获得 通过我们强大的、独立资助的黑色素瘤患者活组织检查计划，部分是利用资金开发的 从这个P01开始。互补表观遗传和转录数据的复杂整合和分析(RNA- 在所有三个项目中生成的)将由共享资源核心来执行 使用最先进的计算分析和验证模型。这些研究的预期结果是 更全面地了解表观遗传和转录调控机制 推动对靶向和免疫癌症疗法的抵制，为临床试验的发展奠定了基础 旨在为晚期黑色素瘤和其他癌症的治疗提供完整和持久的反应。