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

项目摘要 转移性黑色素瘤直到最近还被认为是一种无法治疗的疾病，但发现了 抑制致癌BRAF(V600E)的分子和释放免疫系统对抗 肿瘤给黑色素瘤患者带来了希望。并不是每个患者都会有有意义的治疗益处 对于大多数人来说，从这些治疗和持久的疾病缓解中仍然难以捉摸。造成这一现象的原因包括 无反应或早期复发是一种动态的癌细胞异质性，有助于治疗的结果 具有增强的恶性特征的抗药性肿瘤。为了扩大现有疗法的使用范围，我们建议 以确定可用于组合治疗的替代分子靶点 为可持续的治疗效益做出承诺。具体地说，新陈代谢和表观遗传过程 在高度转移性和慢性BRAF靶向药物适应的黑色素瘤中提供侧枝依赖 在很大程度上是未知的。为此，三分之一的黑色素瘤表现出转录水平的升高。 辅活化子Pgc1α，整合线粒体生物发生和生物能量活动，以确保细胞 生死存亡。在此之前，我们发现Pgc1α的表达与垂直方向之间存在反函数关系 原发黑色素瘤的生长阶段与患者预后不良相关，以及基因靶向 在细胞系模型中，Pgc1α可刺激增强的转移特性。与自适应的职能角色一致 Pgc1α的表达和增强的恶性特征，我们目前的初步数据支持慢性 适应于BRAF靶向药物通过改变其组蛋白标记来沉默Pgc1α的表达 启动子区域。我们现在建议寻找减弱前列腺素C_1α表达的分子机制 LINKS增强了对BRAF靶向药物的转移扩散和慢性适应。在综合学习计划中 这包括临床黑色素瘤标本，已建立的细胞系和体内肿瘤模型，实验 设计的重点是两个目标：1)确定抑制Pgc1α表达的表观遗传机制 对靶向BRAF(V600E)治疗的慢性适应；以及2)确定侧枝代谢和表观遗传学 对靶向BRAF(V600E)治疗的慢性适应造成的脆弱性。这些措施的结果 研究将确定代谢物和表观遗传调节因子在替代的pgc1α- 依赖表观遗传状态。成功完成拟议的研究计划可能有助于预测患者在 增加了临床风险，并提供了打破对BRAF靶向药物的长期适应的手段。

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.