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才被认为是一种无法治愈的疾病，但小的 抑制致癌BRAF（V600 E）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。并非每个患者都能获得有意义的治疗益处 对于大多数人来说，这些治疗和持久的疾病缓解仍然是难以捉摸的。的原因之一 无反应或早期复发是一种动态的癌细胞异质性， 具有增强的恶性特征的耐药肿瘤。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开发的替代分子靶点， 有望获得持续治疗益处。特别是代谢和表观遗传过程 在高转移性和慢性BRAF靶向药物适应性黑色素瘤中提供侧支依赖性 基本上是未知的。为此，三分之一的黑色素瘤显示转录因子的表达增强， 辅激活因子PGC 1 α整合线粒体生物合成和生物能活性，以确保细胞 生存以前我们发现PGC 1 α表达和垂直方向之间存在反函数关系， 与患者预后不良相关的原发性黑色素瘤内的生长阶段，以及 PGC 1 α在细胞系模型中引起转移特性增强。与适应性的功能角色一致 PGC 1 α表达和恶性特征增强，我们目前的初步数据支持， 对BRAF靶向药物的适应通过改变其整个组织中的组蛋白标记来沉默PGC 1 α表达。 启动子区我们现在建议寻找减弱PGC 1 α表达的分子机制， 链接增强了转移扩散和对BRAF靶向药物的慢性适应。在综合研究计划中 包括临床黑色素瘤标本、已建立的细胞系和体内肿瘤模型， 设计集中在两个目标：1）确定在生长过程中沉默PGC 1 α表达的表观遗传机制， 慢性适应靶向BRAF（V600 E）治疗;和2）识别侧支代谢和表观遗传 长期适应靶向BRAF（V600 E）治疗所产生的脆弱性。这些成果 研究将确定代谢物和表观遗传调节剂，这些调节剂引起替代PGC 1 α- 依赖的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 提高临床风险，并提供打破对BRAF靶向药物的慢性适应的手段。

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.