Enhancer RNA Therapy

项目摘要/摘要 KRAS、BRAF和EGFR的激活突变是导致大量致命人类 癌症。这些基因中的一个错义氨基酸突变会导致多种来源的癌症，包括 大量的胰腺癌、肺癌、皮肤癌和结直肠癌。受影响的一般信号通路 这些突变，即所谓的RAS-RAF-MEK-ERK通路(ERK信号)，是药物设计的主要靶点 由制药公司提供。然而，无论分子靶点(激活的BRAF或EGFR，对于 例如)，由于几乎所有病例都出现了耐药性，这一做法受到了阻碍。至 应对这一重要的人类疾病需要新的开创性的非常规方法来 癌症治疗。我们建议建立一种潜在的变革性方法来治疗这些癌症， 我们称之为“增强型RNA疗法”。事实上，我们相信这项计划将适用于广泛的 人类疾病的谱系。 我们的建议取决于我们对增强子RNA(ERNA)功能重要性的发现；非编码 从组织和疾病特异性增强子转录而来的RNA。增强剂是DNA元素，它可以 管理发育和疾病期间基因表达的空间和时间调节。反常的 增强剂的调控被认为是癌症发生和发展的关键事件。我们的目标是 靶向疾病诱导的eRNA沉默致癌基因作为癌症的变革性治疗 通过激活KRAS、BRAF和EGFR突变而诱导。我们将编制一份疾病诱发地图集。 具有激活KRAS和BRAF突变的多种癌症的增强剂。然后我们将在功能上 使用基因和功能方法来表征这些癌症诱导的增强剂。最后，在 与ISIS制药公司合作，我们将开发衍生反义寡核苷酸(ASO)，这将 在体内中和致癌eRNAs，允许组织特异性地抑制致病基因的表达 癌症。因此，我们建议研究‘增强型RNA疗法’的可行性，使用癌症 激活ERK信号通路突变作为模型系统。

Project Summary/Abstract Activating mutations in KRAS, BRAF and EGFR are the underling cause of a large number of deadly human cancers. A single missense amino acid mutation in these genes causes cancers of diverse origins including a large number of pancreatic, lung, skin, and colorectal cancers. The general signaling pathway affected by these mutations, the so-called RAS-RAF-MEK-ERK pathway (ERK signaling), is a major target of drug design by pharmaceutical companies. However, regardless of the molecular target (activated BRAF or EGFR, for example), this approach has been hindered due to the emergence of drug resistance in nearly all cases. To tackle this important human disease there is a need for new groundbreaking unconventional approach to cancer treatment. We propose to establish a potentially transformative approach to treating these cancers, which we refer to as "Enhancer RNA Therapy". Indeed, we believe this plan will be applicable to a wide spectrum of human diseases. Our proposal hinges on our discovery of the functional importance of enhancer RNAs (eRNAs); noncoding RNAs that are transcribed from tissue and disease-specific enhancers. Enhancers are DNA elements that govern spatial and temporal regulation of gene expression during development and disease. Aberrant regulation of enhancers is considered to be a key event in the genesis and progression of cancer. We aim to target disease-induced eRNAs to silence cancer-causing genes as a transformative treatment in cancers induced by activating mutations of KRAS, BRAF and EGFR. We will develop an atlas of disease-induced enhancers in multiple cancers with activating mutations in KRAS and BRAF. We will then functionally characterize these cancer-induced enhancers using genetic and functional approaches. Finally, in collaboration with Isis Pharmaceuticals, we will develop derivatized anti-sense oligonucleotides (ASOs) that will neutralize the oncogenic eRNAs in vivo allowing for tissue specific inhibition of pathogenic gene expression in cancer. We therefore propose to investigate the feasibility of 'Enhancer RNA Therapy' using cancers with activating mutations in ERK signaling pathway as a model system.