Understanding the regulatory role and therapeutic potential of long non-coding RNAs in metastatic colorectal cancer

了解长链非编码 RNA 在转移性结直肠癌中的调节作用和治疗潜力

• 批准号: 10186713
• 负责人: Jessica Silva-Fisher
• 金额: $ 18.95万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186713
• 关键词: Address; Adjuvant Therapy; Advisory Committees; Antisense Oligonucleotides; Automobile Driving; Award; Binding Proteins; Biological Assay; Biological Markers; Cells; Cessation of life; ChIP-seq; Clinical; Clinical Trials; Colon Carcinoma; Colorectal Cancer; Data; Data Analyses; Development; Diagnostic; Disease-Free Survival; Distant; Distant Metastasis; Educational process of instructing; Epigenetic Process; FDA approved; Foundations; Gene Expression; Genes; Genetic Markers; Genetic Transcription; Goals; Grant; Invaded; K22 Award; Knowledge; Laboratories; Lead; Leadership; Manuscripts; Mentors; Mentorship; Modeling; Monitor; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Primary Neoplasm; Prognosis; Prognostic Marker; Proteins; Publications; RNA; RNA Binding; Regulation; Research; Resistance; Role; Running; Sampling; Sequence Analysis; Tail; Therapeutic; Time; Tissues; Topoisomerase; Topoisomerase Inhibitors; Training; Translational Research; Untranslated RNA; Veins; antisense nucleic acid; biomarker discovery; career; clinically significant; cohort; colon cancer metastasis; colon cancer patients; colorectal cancer progression; differential expression; epigenetic regulation; experience; improved; improved outcome; in vivo; in vivo Model; insight; locked nucleic acid; metastatic colorectal; nano-string; new therapeutic target; novel; prognostic; programs; recruit; skills; targeted treatment; therapeutic RNA; therapeutic evaluation; therapeutic target; transcriptome; transcriptome sequencing; translational impact; translational research program; translational scientist; treatment response; tumor; tumorigenesis

Project Summary/Abstract The overall research goal of this proposal is to elucidate the mechanisms driving mCRC to better assess the critical need for discovery of biomarkers and targeted therapies. Although early stage colorectal cancer (CRC) is curable with surgery and adjuvant therapy, metastatic CRC (mCRC) is usually lethal. Despite advances in our understanding of primary CRC oncogenesis, the mechanisms by which CRC becomes metastatic and leads to patient death is poorly characterized. In addition, the lack of reliable biomarkers to predict development of mCRC and select patients for further treatment is a critical barrier. To address this critical knowledge gap, our proposal seeks to understand how long non-coding RNAs (lncRNAs) enable primary tumors to invade and metastasize to develop improved diagnostics and therapeutics. Therefore, we performed transcriptome analysis of 37 patient matched normal, primary, and distant metastatic colorectal cancer tissues to discover 148 differentially expressed (DE) RNA Associated with Metastasis (RAMS). Notably, the top up-regulated novel candidate, RAMS11, (i) is associated with poor survival, (ii) induces invasion in vitro and in vivo, (ii) increases resistance to topoisomerase inhibitors, (iii) interacts with chromobox homology 4 (CBX4), and (iv) and can be targeted with locked nucleic acids in vitro. This serves as the rationale for our hypothesis that RAMS11 may serve as a prognostic biomarker associated with poor outcome by interacting with CBX4 to epigenetically regulate genes and can be therapeutically targeted in mCRC. To demonstrate this, Aim 1 will evaluate RAMS11 as a prognostic biomarker associated with poor long-term outcome. Aim 2 will characterize RAMS11-dependant CBX4 regulation. Lastly, Aim 3 will evaluate RAMS11 therapeutic potential. This proposal will establish the importance of RAMS11 as a master epigenetic regulator to promote colon cancer metastasis. Furthermore, this research is of translational impact by evaluating the prognostic and therapeutic potential of targeting RAMS11 directly with locked nucleic acid antisense oligonucleotides.

项目总结/文摘