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

基本信息

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
项目类别：
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

项目摘要

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.

总结该提案续签P01 CA163222的总体目标是进一步改善转移的反应黑色素瘤通过靶向异常肿瘤来绘制靶向靶向和免疫检查点疗法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。尽管这些革命性疗法为黑色素瘤提供了重大改善成果，以及过去五年来的进步（在这个计划项目中），其他人已经实质改善了克服治疗性抗性的前景，大多数患者仍然会经历最终的经历疾病的进展和死亡。即使我们在识别抵抗机制方面取得了重大成功和新型的潜在治疗策略，迫切需要发现其他机制和对黑色素瘤的靶向和免疫疗法的获得和固有抗性的潜在靶标。我们的当前方法结合了调查人员在此计划项目下发现的机械洞察力赠款（PPG）和其他群体，即遗传像差在表观遗传调节中的重要性抵抗治疗的机械，至少部分通过重塑肿瘤免疫微环境和AS 克服电阻的潜在目标。该提案中的三个研究项目部分描述了未发现的机制，不同的表观遗传和转录调节剂驱动黑色素瘤抗性进行治疗，可能是针对治疗的。这些调节器包括基因组拷贝数的收益和新描述的组蛋白甲基转移酶G9A的功能收益突变，在染色质中重新定位 ETS转录因子家族成员ETV1和PBAF成分的功能丧失突变 SWI/SNF染色质重塑配合物。这些调节剂将在体外和多个中进行研究临床前模型，以更深入地理解其抵抗机制，尤其是他们的抵抗机制对抗肿瘤免疫反应的影响，以及确定对反应的生物标志物并评估针对治疗策略的可行性。识别阻力介质和生物标志物在人类前和治疗的黑色素瘤活检中将得到佐证的反应，很容易获得通过我们强大的，独立资助的黑色素瘤患者活检计划，部分开发了资金从这个P01。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对表观遗传和转录调节剂的机制有更完整的理解对靶向和免疫癌症疗法的耐药性，为发展临床试验奠定了基础旨在为晚期黑色素瘤和其他癌症提供对疗法的完整耐用反应。