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.

总体汇总 P01 CA 163222更新提案的总体目标是进一步改善转移性肿瘤的缓解。 黑色素瘤MAP激酶通路靶向和免疫检查点疗法，通过靶向异常肿瘤- 基因表达的内在表观遗传调控，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， 在过去的五年里，我们（在这个计划项目中）和其他人的成果和进步， 虽然改善了克服治疗抵抗的前景，但大多数患者仍然会经历最终的治疗抵抗。 疾病进展和死亡率。即使我们在确定耐药机制方面取得了重大成功， 新的潜在的治疗策略，仍然迫切需要发现其他机制， 在黑色素瘤的靶向和免疫疗法的获得性和内在抗性中的潜在靶点。我们 目前的方法结合了本计划项目下调查人员发现的机械见解 格兰特（PPG）和其他团体，即遗传畸变的重要性，在表观遗传调控 至少部分地通过重塑肿瘤免疫微环境， 克服耐药性的潜在目标。本提案中的三个研究项目部分描述了 揭示了不同的表观遗传和转录调节因子驱动黑色素瘤抗性的机制 可能是治疗的靶点这些调节因子包括基因组拷贝数的增加， 新描述的组蛋白甲基转移酶G9 a的功能获得性突变， ETS转录因子家族成员ETV 1，以及 SWI/SNF染色质重塑复合物。这些调节剂将在体外和多个 临床前模型，以便更深入地了解其耐药机制，特别是 对抗肿瘤免疫应答的影响，以及鉴定应答的生物标志物和评估 治疗策略的可行性。耐药介质和生物标志物的鉴定 缓解将在人类治疗前和治疗中黑色素瘤活检中得到证实，这些活检可随时获得 通过我们强大的、独立资助的黑色素瘤患者活检项目， 从P01开始互补的表观遗传和转录数据（RNA-RNA）的复杂整合和分析 seq、ATAC-seq和ChIP-seq）将由共享资源核心执行 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节因子 推动对靶向和免疫癌症疗法的耐药性，为临床试验的发展奠定基础 旨在为晚期黑色素瘤和其他癌症的治疗提供完全和持久的反应。