Enhancer RNA Therapy

增强子RNA疗法

• 批准号: 9981665
• 负责人: RAMIN SHIEKHATTAR
• 金额: $ 107.45万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981665
• 关键词: Affect; Amino Acids; Antisense Oligonucleotides; Atlases; BRAF gene; Biological Models; Cancer Etiology; Collaborations; Colorectal Cancer; DNA; Development; Disease; Drug Design; Drug Targeting; Drug resistance; Elements; Enhancers; Epidermal Growth Factor Receptor; Event; Gene Expression; Gene Expression Regulation; Genes; Genetic; Human; Inflammatory; KRAS2 gene; MEKs; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Molecular Target; Mutation; Oncogenic; Outcome; Pathogenicity; Pathway interactions; Pharmacologic Substance; Pharmacotherapy; RNA; Ras/Raf; Regulation; Resistance; Signal Pathway; Signal Transduction; Skin Cancer; Tissues; Untranslated RNA; cancer therapy; human disease; in vivo; novel therapeutic intervention; tumor progression

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.

项目摘要/摘要 在KRAS，BRAF和EGFR中激活突变是大量致命人类的基础原因 癌症。这些基因中的单个错义氨基酸突变导致各种起源的癌症，包括a 大量胰腺，肺，皮肤和结直肠癌。受影响的一般信号通路 这些突变，即所谓的Ras-Raf-Mek-ERK途径（ERK信号），是药物设计的主要目标 由制药公司。但是，无论分子靶标如何（激活的BRAF或EGFR） 例如），由于几乎所有情况下的耐药性出现，这种方法受到阻碍。到 应对这种重要的人类疾病，需要采取新的开创性的非常规方法 癌症治疗。我们建议建立一种潜在的变革方法来治疗这些癌症， 我们称为“增强子RNA疗法”。确实，我们认为该计划将适用于广泛的 人类疾病的范围。 我们的建议取决于我们发现增强器RNA（ERNAS）功能重要性的功能重要性；非编码 从组织和疾病特异性增强子转录的RNA。增强子是DNA元素 控制发育和疾病期间基因表达的空间和时间调节。异常 增强子的调节被认为是癌症起源和进展中的关键事件。我们的目标 靶向疾病引起的ERNAS，使癌症的基因沉默，作为癌症的转化治疗 通过激活KRAS，BRAF和EGFR的突变引起。我们将开发一个疾病引起的地图集 在KRAS和BRAF中具有激活突变的多种癌症中的增强剂。然后，我们将在功能上 使用遗传和功能方法来表征这些癌症诱导的增强子。最后，在 与ISIS制药的合作，我们将开发衍生化的反义寡核苷酸（ASO） 中和体内的致癌ERNAS，允许组织特异性抑制致病基因表达 癌症。因此，我们建议使用具有 将ERK信号通路中的突变作为模型系统。