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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要该提案的总体研究目标是阐明驱动MCRC的机制以更好地评估发现生物标志物和靶向疗法的临界需求。虽然早期结直肠癌癌症（CRC）可通过手术和辅助治疗，转移性CRC（MCRC）通常是致命的。尽管我们对主要CRC肿瘤发生的进步，CRC成为的机制转移性和导致患者死亡的特征很差。此外，缺乏可靠的生物标志物预测MCRC和选择患者进行进一步治疗是关键障碍。解决这个问题批判性知识差距，我们的提议试图了解非编码RNA（LNCRNA）启用多长时间原发性肿瘤侵入和转移以发展诊断和治疗疗法。因此，我们对37例患者进行了转录组分析，匹配正常，原发性和遥远的转移性结直肠癌发现与转移（RAMS）相关的148个差异表达的（DE）的癌组织。尤其，顶级上调的新型候选人RAMS11，（i）与存活不良有关，（ii）在体外诱导入侵在体内，（ii）增加了对拓扑酶抑制剂的抗性，（iii）与Chromobox同源性4相互作用4 （CBX4）和（IV），可以在体外用锁定的核酸靶向。这是我们的理由 RAMS11可以通过相互作用而成为与结果不佳相关的预后生物标志物的假设用CBX4进行表观遗传调节基因，并且可以在MCRC中进行治疗。为了证明这一点， AIM 1将评估RAMS11作为与差的长期结果相关的预后生物标志物。 AIM 2意志表征RAMS11依赖的CBX4调节。最后，AIM 3将评估RAMS11治疗潜力。该建议将确定RAMS11作为促进结肠的大师表观遗传调节剂的重要性癌症转移。此外，这项研究通过评估预后和直接用锁定的核酸反义寡核苷酸直接靶向RAMS11的治疗潜力。