Enhancer RNA Therapy

增强子RNA疗法

• 批准号: 10219187
• 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/10219187
• 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; refractory cancer; 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.

项目总结/摘要 KRAS、BRAF和EGFR的激活突变是导致大量致命人类肿瘤的潜在原因。 癌的这些基因中的单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、皮肤癌和结肠直肠癌。一般的信号通路受 这些突变，即所谓的RAS-RAF-MEK-ERK通路（ERK信号传导），是药物设计的主要靶点 制药公司。然而，无论分子靶点（激活的BRAF或EGFR， 例如，由于几乎所有病例都出现了耐药性，这一方法受到了阻碍。到 为了对付这种重要人类疾病，需要新的突破性的非常规方法， 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， 我们将其称为“增强子RNA疗法”。事实上，我们相信这项计划将适用于广泛的 人类疾病谱。 我们的建议取决于我们发现增强子RNA（eRNA）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元件， 在发育和疾病过程中控制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发生和发展中的关键事件。我们的目标是 靶向疾病诱导eRNA沉默致癌基因作为癌症的变革性治疗 由KRAS、BRAF和EGFR的激活突变诱导。我们将建立一个疾病诱发的 KRAS和BRAF中具有激活突变的多种癌症中的增强子。我们将在功能上 使用遗传和功能方法表征这些癌症诱导增强子。最后在 与Isis Pharmaceuticals合作，我们将开发衍生化反义寡核苷酸（ASO）， 中和体内致癌eRNA，从而允许组织特异性抑制体内致病基因表达， 癌因此，我们建议研究“增强子RNA疗法”使用具有以下特征的癌症的可行性： 激活ERK信号通路中的突变作为模型系统。