MicroRNA and colorectal cancer chemoprevention

MicroRNA 与结直肠癌化学预防

基本信息

批准号：
9313603
负责人：
Yaguang Xi
金额：
$ 33.4万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9313603
关键词：
Address Adenomatous Polyposis Coli Adverse effects American Cancer Society Amides Angiogenesis Inhibition Animal Model Antineoplastic Agents Apoptosis Apoptotic Aspirin BCL2 gene BIRC4 gene Benzylamines Biological Assay Biological Markers Biological Process Breast Cancer Cell Cancer Patient Cause of Death Cell Proliferation Cessation of life Chemoprevention Chemopreventive Agent Chemoprotection Clinical Research Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Colonic Neoplasms Colorectal Colorectal Cancer Colorectal Neoplasms Data Development E-Cadherin Epidemiologic Studies Epithelial Gene Expression General Population Genes Health Human Image Immunohistochemistry In Situ Hybridization In Vitro Incidence Individual Induction of Apoptosis Inhibition of Apoptosis Malignant Neoplasms Measures Mediating Mediation Mesenchymal Meta-Analysis Metastasis Induction MicroRNAs Molecular Neoplasm Metastasis Non-Steroidal Anti-Inflammatory Agents Oncogenic Pathway interactions Pharmaceutical Preparations Play Premalignant Prevention Prostaglandin-Endoperoxide Synthase Publications RNA Processing Randomized Controlled Clinical Trials Regulator Genes Reporting Research Risk Role Signal Pathway Snails Sulindac Sulindac Sulfide System Technology Tissue Microarray Toxic effect Transcription Repressor/Corepressor Tumor Cell Invasion Tumor Suppressor Proteins United States Untranslated RNA adenoma advanced disease anticancer activity base cancer cell cancer chemoprevention cancer initiation cancer statistics cell growth chromatin immunoprecipitation clinically relevant colon cancer patients colorectal cancer prevention cytotoxic effective therapy genome editing improved in vitro Model in vivo mouse model neoplastic cell new therapeutic target novel pre-clinical preclinical study prevent response tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): According to the latest report of cancer statistics by American Cancer Society, colorectal cancer remains a leading cause of death from cancer in the United States. Therefore, there is still an unmet need to develop safer and more efficacious agents for treatment and prevention of colorectal cancer. Numerous studies report that the nonsteroidal anti-inflammatory drug (NSAID), sulindac is highly effective for the treatment of precancerous adenomas in individuals with familial adenomatous polyposis and shows promising anticancer activity in preclinical animal models; however, the adverse side effects resulting from cyclooxygenase (COX) inhibition limit the long-term use of sulindac for chemoprevention. Our previous studies reported that two non- COX inhibitory derivatives, sulindac sulfide amide (SSA) and sulindac benzylamine (SBA), can inhibit colorectal tumor cell growth with better potency and improved efficacy when compared to sulindac sulfide (SS).These results imply that anticancer activity of sulindac might attribute to other underlying mechanisms distinct from COX inhibition. In this application, we will aim at anticancer activity of SSA and SBA in prevention of colorectal tumor progression and metastasis, and focus on mechanism of action. Our recent results show that SS at sub-cytotoxic concentrations can efficiently inhibit the invasion of human colon tumor cells, which suggest that this drug may inhibit biological processes associated with metastasis. The mechanism of action appears to involve microRNAs (miRNAs), which are a set of small non-coding RNA molecules acting as master regulators of gene expression. A tumor suppressor miRNA, miR-200, was found to be up-regulated by SS and its non-COX inhibitory derivatives through the signaling pathway mediated by the transcriptional repressor snail. Given the documented tumor suppressive roles in promotion of apoptosis and inhibition of metastasis, we hypothesize that miR-200 is a key factor to mediate the non-COX anticancer activity of SSA and SBA for prevention of colorectal cancer. Three specific aims are proposed to address this hypothesis are: (1) to study the mechanistic basis of miR-200 in mediation of anticancer activities of SSA and SBA in vitro; (2) to study the role of miR-200 in mediating anticancer activities of sulindac in vivo; (3) to assess the clinical relevance of snail/miR-200/E-cadherin to human colorectal cancer progression. This application is being submitted in response to PA-12-213 and will address two research objectives: "determine the molecular pathways targeted by non-coding RNAs (ncRNAs) that predispose to cancer initiation or progression" and "determine whether interfering with oncogenic ncRNAs processing, target selection, or associated pathways prevent cancer progression". The proposed studies have the potential to impact human health by: 1) providing a mechanistic rationale in support of an ongoing national clinical trial studying prevention of colorectal cancer metastasis by sulindac; 2) evaluating novel non-COX inhibitory directives of sulindac to accelerate their preclinical development; and 3) identifying new therapeutic targets and/or biomarkers for clinical trials.

描述（由申请人提供）：根据美国癌症学会的癌症统计数据的最新报告，大肠癌仍然是美国癌症死亡的主要原因。因此，仍然需要开发更安全，更有效的药物来治疗和预防结直肠癌。大量研究报告说，非甾体类抗炎药（NSAID），Sulindac对于患有家族性腺瘤性息肉病的个体的癌前腺瘤非常有效，并且在临床前动物模型中显示出有希望的抗癌活性。然而，环氧酶（COX）抑制作用引起的不良副作用限制了苏莱氏菌进行化学预防的长期使用。我们先前的研究报告说，两种非COX抑制衍生物，硫化硫酸硫酸酰胺（SSA）和硫酸磺糖苄胺（SBA）可以抑制结直肠肿瘤细胞的生长，具有更好的效能和改善的功效，而与硫酸硫酸硫酸硫化物（SS）相比，这可能是从硫酸硫酸硫化物（SSS）中抑制了硫酸的抗cox，而抗硫酸可能会造成其他不足的作用。在此应用中，我们将针对 SSA和SBA预防结直肠肿瘤的进展和转移，并专注于作用机理。我们最近的结果表明，亚周毒浓度的SS可以有效抑制人类结肠肿瘤细胞的侵袭，这表明该药物可以抑制与转移相关的生物学过程。作用机理似乎涉及microRNA（miRNA），后者是一组小的非编码RNA分子，充当基因表达的主调节剂。发现肿瘤抑制miRNA miR-200，被SS及其非Cox抑制衍生物上调，通过转录阻遏蜗牛介导的信号传导途径。鉴于所记载的肿瘤抑制在促进凋亡和抑制转移方面的作用，我们假设miR-200是介导SSA和SBA的非Cox抗癌活性以预防结直肠癌的关键因素。提出了三个特定的目的来解决这一假设：（1）研究miR-200在体外SSA和SBA抗癌活性中的机理基础；（2）研究miR-200在体内硫酸硫酸的抗癌活性中的作用；（3）评估蜗牛/miR-200/e-钙粘着蛋白与人结直肠癌进展的临床相关性。该应用是针对PA-12-213提交的，将解决两个研究目标：“确定非编码RNA（NCRNA）靶向的分子途径，这些途径易于癌症的起始或进展”，并确定干扰致癌NCRNAS处理，靶标的选择，相关途径，或者是确定了对癌症的癌症的疾病的促进，或者是否会防止癌症的进展。拟议的研究有可能通过以下方式影响人类健康：1）提供机械基本原理，以支持正在进行的国家临床试验，该试验研究了苏莱达克对结直肠癌转移的预防； 2）评估新型的非cox抑制指令，以加速其临床前的发育； 3）确定用于临床试验的新的治疗靶标和/或生物标志物。