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.

项目概要/摘要该提案的总体研究目标是阐明驱动 mCRC 更好地评估的机制发现生物标志物和靶向治疗的迫切需要。虽然早期结直肠癌症（CRC）可以通过手术和辅助治疗治愈，转移性CRC（mCRC）通常是致命的。尽管我们对原发性结直肠癌肿瘤发生、结直肠癌变成的机制的理解取得了进展转移性并导致患者死亡的特征尚不清楚。此外，缺乏可靠的生物标志物预测 mCRC 的发展并选择患者进行进一步治疗是一个关键障碍。为了解决这个问题关键的知识差距，我们的提案旨在了解非编码 RNA (lncRNA) 能够持续多久原发性肿瘤侵袭和转移，以开发改进的诊断和治疗方法。因此，我们对 37 名匹配的正常、原发性和远处转移性结直肠癌患者进行转录组分析癌症组织发现了 148 个与转移相关的差异表达 (DE) RNA (RAMS)。尤其，上调最多的新型候选药物 RAMS11，(i) 与较差的生存率相关，(ii) 诱导体外侵袭在体内，(ii) 增加对拓扑异构酶抑制剂的抵抗力，(iii) 与 chromobox 同源性相互作用 4 (CBX4) 和 (iv) 并且可以在体外用锁定核酸靶向。这就是我们的理由假设 RAMS11 可能通过相互作用作为与不良结果相关的预后生物标志物与 CBX4 一起对基因进行表观遗传调节，并可作为转移性结直肠癌 (mCRC) 的治疗靶点。为了证明这一点，目标 1 将评估 RAMS11 作为与长期预后不良相关的预后生物标志物。目标2将表征 RAMS11 相关的 CBX4 调节。最后，目标 3 将评估 RAMS11 的治疗潜力。该提案将确立 RAMS11 作为主要表观遗传调节因子促进结肠癌的重要性癌症转移。此外，这项研究通过评估预后和治疗具有转化影响。使用锁定核酸反义寡核苷酸直接靶向 RAMS11 的治疗潜力。