Metabolic and epigenetic dependencies in melanomas during metastasis and targeted-drug resistance

黑色素瘤转移和靶向药物耐药过程中的代谢和表观遗传依赖性

• 批准号: 10599853
• 负责人: Pere Puigserver
• 金额: $ 44.15万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599853
• 关键词: Acute; Address; Applications Grants; Attenuated; Automobile Driving; BRAF gene; Bioenergetics; Biogenesis; Blocking Antibodies; Cell Line; Cells; Chromatin; Chronic; Clinical; Clinical Management; Data; Dependence; Disease; Disease remission; Drug Targeting; Drug resistance; EZH2 gene; Ensure; Enzymes; Epigenetic Process; Experimental Designs; Failure; Gene Expression; Genetic; Growth; Heterogeneity; Histones; Human; Immune system; In Vitro; Invaded; Link; Malignant Neoplasms; Melanoma Cell; Metabolic; Metabolism; Metastatic Melanoma; Mitochondria; Modeling; Molecular; Molecular Target; Neoplasm Metastasis; Oncogenes; Oncogenic; Outcome Study; Patients; Pattern; Pharmaceutical Preparations; Primary Lesion; Process; Promoter Regions; Refractory; Relapse; Reporting; Repression; Resistance; Role; Site; Skin Cancer; Specimen; Therapeutic; Transcription Coactivator; Treatment outcome; Variant; Vertical Growth Phase; cancer cell; clinical risk; clinically relevant; combinatorial; established cell line; expectation; immune checkpoint; in vivo; melanoma; patient prognosis; promoter; recruit; response; small molecule; targeted treatment; therapy resistant; trait; transcriptome; treatment response; tumor; tumor behavior; whole genome

Project Summary Metastatic melanoma was until recently considered an untreatable disease, but the discovery of small molecules that inhibit oncogenic BRAF(V600E) and approaches that unleash the immune system against tumors have brought hope to melanoma patients. Not every patient will have meaningful therapeutic benefit from these treatments and durable disease remission remains elusive for most. Among the causes of the failure to respond or early relapse is a dynamic cancer cell heterogeneity that facilitates outgrowth of therapy resistant tumors with enhanced malignancy traits. In order to extend the use of current therapies, we propose to identify alternative molecular targets that could be harnessed for combinatorial treatment exploit and might hold promise for sustainable therapeutic benefit. Specifically, whether metabolic and epigenetic processes provide collateral dependencies within highly metastatic and chronic BRAF-targeted drug-adapted melanomas is largely unknown. To this end, a third of melanomas display heightened expression of the transcriptional coactivator PGC1α that integrates mitochondrial biogenesis and bioenergetic activity to ensure cellular survival. Previously we found an inverse functional relationship between PGC1α expression and vertical growth phase within primary melanoma that associates with poor patient prognosis, and genetic targeting of PGC1α provoked enhanced metastatic traits in cell line models. Consistent with a functional role for adaptive expression of PGC1α and enhanced malignancy traits, our current preliminary data supports that chronic adaptation to BRAF-targeted drugs silences PGC1α expression through altered histone marks across its promoter region. We now propose to seek the molecular mechanisms that attenuate PGC1α expression that links enhanced metastatic spread and chronic adaptation to BRAF-targeted drugs. In an integrated study plan that includes clinical melanoma specimens, established cell lines and in vivo tumor modeling, the experimental design is focused on two aims: 1) to determine epigenetic mechanisms that silence PGC1α expression during chronic adaptation to targeted BRAF(V600E) treatment; and 2) to identify collateral metabolic and epigenetic vulnerabilities arising from chronic adaptation to targeted BRAF(V600E) treatment. Outcomes from these studies will identify metabolites and epigenetic regulators that provoke vulnerabilities within alternate PGC1α- dependent epigenetic states. Successful completion of the proposed study plan may help predict patients at heightened clinical risk as well as provide means to break chronic adaptation to BRAF-targeted drugs.

项目摘要 直到最近，转移性黑色素瘤被认为是一种不可治疗的疾病，但发现很小 抑制致癌BRAF（V600E）的分子，并接近释放免疫系统的 肿瘤给黑色素瘤患者带来了希望。并非每个患者都会有有意义的治疗益处 从这些治疗方法中，对于大多数人来说，仍然难以捉摸。在 无法做出反应或早期缓解是动态癌细胞的异质性，可促进治疗的生长 具有增强的恶性特征的抗性肿瘤。为了扩展当前疗法的使用，我们建议 确定可以利用组合治疗利用的替代分子靶标的 对可持续治疗益处保持承诺。具体而言，是否代谢和表观遗传过程 在高度转移和慢性BRAF靶向药物适应的黑色素瘤中提供附带依赖性 在很大程度上未知。为此，三分之一的黑色素瘤显示了转录的表达增强 结合线粒体生物发生和生物能活性以确保细胞的共激活因子PGC1α 生存。以前我们发现PGC1α表达与垂直之间的功能关系逆关系 原发性黑色素瘤内的生长阶段与患者提示不佳，遗传靶向 PGC1α在细胞系模型中引发了增强的转移性特征。与适应性的功能作用一致 PGC1α的表达和增强的恶性特征，我们当前的初步数据支持慢性 适应对BRAF靶向药物通过改变其跨越组蛋白标记的pGC1α表达沉默 启动子区域。现在，我们建议寻求减弱PGC1α表达的分子机制 链接增强了转移扩散和对BRAF靶向药物的长期适应性。在综合学习计划中 其中包括临床黑色素瘤标本，已建立的细胞系和体内肿瘤建模，实验性 设计的重点是两个目的：1）确定表观遗传机制，使PGC1α在 长期适应靶向BRAF（V600E）治疗； 2）确定副作用和表观遗传 长期适应针对靶向BRAF（V600E）治疗的脆弱性。这些结果 研究将确定在替代PGC1α-替代脆弱性的代谢产物和表观遗传调节剂 依赖的表观遗传态。成功完成拟议的研究计划可能有助于预测患者 临床风险增加，并提供了破坏对BRAF靶向药物的慢性适应性的方法。