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.

项目概要/摘要 KRAS、BRAF 和 EGFR 的激活突变是导致人类大量死亡的根本原因 癌症。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 大量胰腺癌、肺癌、皮肤癌和结直肠癌。影响的一般信号通路 这些突变，即所谓的 RAS-RAF-MEK-ERK 通路（ERK 信号传导），是药物设计的主要目标 由制药公司。然而，无论分子靶点（激活的 BRAF 或 EGFR） 例如），由于几乎所有情况下都出现耐药性，这种方法受到了阻碍。到 解决这一重要的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，我们相信该计划将适用于广泛的 人类疾病谱。 我们的提议取决于我们对增强子 RNA (eRNA) 功能重要性的发现；非编码 由组织和疾病特异性增强子转录的 RNA。增强子是 DNA 元件， 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发生和进展的关键事件。我们的目标是 靶向疾病诱导的 eRNA 来沉默致癌基因，作为癌症的变革性治疗方法 由 KRAS、BRAF 和 EGFR 的激活突变诱导。我们将开发疾病诱发图谱 多种癌症中的增强子，具有 KRAS 和 BRAF 激活突变。然后我们将在功能上 使用遗传和功能方法表征这些癌症诱导的增强子。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，从而对致病基因表达进行组织特异性抑制 癌症。因此，我们建议研究使用具有以下特征的癌症进行“增强子 RNA 疗法”的可行性： 激活 ERK 信号通路突变作为模型系统。