MiR-17 mediates sulindac anti-metastatic activity in human colorectal cancer

MiR-17 介导舒林酸在人结直肠癌中的抗转移活性

• 批准号: 10258119
• 负责人: Yaguang Xi
• 金额: --
• 依托单位: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10258119
• 关键词: Address; Animal Model; Antineoplastic Agents; Aspirin; Biogenesis; Biological Markers; Blood specimen; Cancer Control; Cancer Etiology; Cancer Intervention; Cancer Patient; Cardiovascular system; Cessation of life; Characteristics; Clinic; Clinical; Clinical Trials; Colon; Colorectal Cancer; Data; Development; Disease; Distant; Distant Metastasis; Dose; Experimental Animal Model; FDA approved; Familial Adenomatous Polyposis Syndrome; Forms Controls; Future; General Population; Generic Drugs; Genes; Healthcare; Human; Incidence; Individual; Lead; Lesion; Liver; Longevity; Lung; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical center; Meta-Analysis; Metastatic Adenocarcinoma; MicroRNAs; Military Personnel; Modeling; Molecular; Mus; Neoplasm Metastasis; Non-Steroidal Anti-Inflammatory Agents; Organ; Patients; Pharmaceutical Preparations; Physicians; Plasma; Polyps; Prostaglandin-Endoperoxide Synthase; Randomized Controlled Clinical Trials; Regulation; Reporting; Resources; Risk; Role; Safety; Sampling; Specimen; Sulindac; Survival Rate; System; Therapeutic; Time; Tissue Microarray; Tissues; Toxic effect; Treatment Efficacy; Tumor Suppressor Proteins; Tumor-Derived; United States; United States Department of Veterans Affairs; Veterans; adenoma; advanced disease; base; cancer cell; cancer chemoprevention; cell motility; colon cancer patients; colorectal cancer metastasis; colorectal cancer prevention; colorectal cancer progression; exosome; implantation; improved; in vivo; innovation; insight; interest; metastatic colorectal; mortality risk; mouse model; novel; patient derived xenograft model; peripheral blood; pharmacokinetics and pharmacodynamics; preclinical study; premalignant; pressure; prevent; rectal; success; systemic toxicity; transcriptome sequencing; tumor; tumor progression; tumorigenesis

PROJECT SUMMARY: In the United States, approximately 3% of cancer patients are being treated in the Veterans Affairs Medical Centers (VAMCs) each year, of which 11% are colon or rectal malignancies. Colorectal cancer (CRC) remains a leading cause of cancer-related death in the United States. Although the overall survival for CRC patients with advanced disease has been dramatically improved over the past decades, the most recently reported 5-year survival rate for patients with stage IV CRC was lower than 14%. To date, there are only a few drugs approved by the FDA to treat CRC patients with advanced disease. Along with new military personnel entering the VA system, physician shortages, and extended lifespan of seniors, the demands on VA health care resources are becoming significant. Therefore, developing more efficacious and safer therapeutics for treating veteran patients could be an economical and feasible strategy to offset the pressure on the VAMCs due to the increasing needs for VA health care. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to significantly reduce the incidence and risk of death from CRC and other forms of cancer. Sulindac, in particular, has been shown to display strong efficacy for the treatment of precancerous lesions in patients with familial adenomatous polyposis by reducing the size and number of polyps as much as 60-70%. These observations are consistent with numerous preclinical studies that have shown the ability of sulindac and other NSAIDs to inhibit tumorigenesis in various experimental animal models involving either early or late-stage diseases. However, the cardiovascular toxicity associated with cyclooxygenase/prostaglandin (COX/PGE) inhibition precludes the long-term use of NSAIDs for cancer indications in the general population. Our preliminary studies support a novel notion that a low dose of sulindac inhibits CRC cell invasion and metastasis with non-COX/PGE inhibition mechanisms involving select miRNAs. Of interest, exosomal miR-17-5p (ES-miR-17-5p), for the first time, was found to act as one of the key mediators targeted and modulated by sulindac to intervene in pre-metastatic niche formation. These data provide an innovative insight into the potential of utilizing low dose sulindac to prevent and block CRC metastatic progression, which has not yet been studied exclusively. We hypothesize that ES-miR-17-5p is intimately involved in the molecular mechanism by which low dose sulindac can delay and potentially block CRC distant metastasis. Three specific aims are proposed in pursuit of our premise to demonstrate a new indication of low dose sulindac in control of metastatic CRC. In Aim 1, we will study a new mechanism involving ES-miR-17-5p in order to understand the inhibitory activity of sulindac in CRC cell motility; in Aim 2, we will determine the role of ES-miR-17-5p in mediating the in vivo anti-metastatic activity of sulindac utilizing animal models; in Aim 3, we will evaluate the clinical utility of miR-17-5p in predicting tumor progression with CRC specimen samples. We expect that our study can support an efficacious and safe option to benefit the veterans with advanced CRC and eventually improve the VA health care.

项目摘要： 在美国，大约3％的癌症患者正在退伍军人事务中接受治疗 每年中心（VAMC），其中11％是结肠或直肠恶性肿瘤。结直肠癌（CRC）仍然存在 美国与癌症相关死亡的主要原因。尽管CRC患者的总生存期 在过去的几十年中，晚期疾病已大大改善，最近报道了5年 IV期CRC患者的存活率低于14％。迄今为止，只有少数药物已批准 由FDA治疗患有晚期疾病的CRC患者。以及进入VA的新军事人员 系统，医师短缺和老年人的寿命延长，对VA医疗保健资源的需求是 变得重要。因此，开发更有效，更安全的治疗疗法，以治疗老将患者 由于需求不断增长，可能是抵消VAMC压力的经济且可行的策略 用于VA医疗保健。 非甾体类抗炎药（NSAID）已显示可显着降低发生率和风险 CRC和其他形式的癌症死亡。尤其是苏琳克已被证明显示出强大的功效 用于治疗家族性腺瘤性息肉病患者的癌前病变，通过降低大小 息肉的数量高达60-70％。这些观察结果与众多临床前研究一致 已经表明硫酸和其他NSAID抑制各种实验动物肿瘤发生的能力 涉及早期或晚期疾病的模型。但是，与相关的心血管毒性 环氧酶/前列腺素（COX/PGE）抑制作用排除了NSAID用于癌症的长期使用 一般人群的适应症。我们的初步研究支持了一个新的观念，即低剂量的苏琳克 用涉及精选miRNA的非Cox/PGE抑制机制抑制CRC细胞侵袭和转移。 感兴趣的是，首次发现外泌体miR-17-5p（ES-MIR-17-5P）是关键介体之一 由Sulindac靶向和调节，以干预替代前转移的细分市场形成。这些数据提供了 创新的洞察力对利用低剂量的硫酸的潜力预防和阻止CRC转移性 进展，尚未仅研究。我们假设ES-MIR-17-5P密切 参与分子机制，低剂量的sulindac可以延迟并可能阻止CRC远处 转移。提出了三个特定的目标，以追求我们的前提，以证明新的迹象 转移性CRC的控制剂量苏氏剂。在AIM 1中，我们将研究涉及ES-MIR-17-5P的新机制 为了理解苏琳克在CRC细胞运动性中的抑制活性；在AIM 2中，我们将确定角色 ES-MIR-17-5P的介导苏氏菌的体内抗转移活性，利用动物模型；在AIM 3中，我们 将评估miR-17-5p在用CRC样品样品预测肿瘤进展方面的临床实用性。我们 期望我们的研究可以支持有效且安全的选择，以使退伍军人通过高级CRC和 最终改善了VA医疗保健。