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.

项目总结： 在美国，大约3%的癌症患者正在退伍军人事务部接受治疗 其中11%是结肠癌或直肠恶性肿瘤。结直肠癌(CRC)残留 这是美国癌症相关死亡的主要原因。尽管结直肠癌患者的总体存活率 在过去的几十年里，晚期疾病有了显著的改善，最近报告的5年 IV期结直肠癌患者的生存率低于14%。到目前为止，只有几种药物获得批准 由FDA用于治疗晚期结直肠癌患者。随着新的军事人员进入退伍军人管理局 制度、医生短缺和老年人寿命延长，对退伍军人管理局卫生保健资源的需求是 变得重要起来。因此，开发更有效、更安全的治疗方法来治疗退伍军人患者 可能是一种经济可行的战略，以抵消日益增长的需求给VAMC带来的压力 退伍军人管理局的医疗保健。 非类固醇抗炎药(NSAIDs)已被证明能显著降低发病率和风险。 死于结直肠癌和其他形式的癌症。尤其是舒林酸，已被证明具有很强的疗效。 缩小体积治疗家族性腺瘤性息肉病癌前病变 息肉的数量高达60%-70%。这些观察结果与大量临床前研究一致。 已显示舒林酸和其他非甾体抗炎药在各种实验动物中抑制肿瘤形成的能力 涉及早期或晚期疾病的模型。然而，与之相关的心血管毒性 环氧合酶/前列腺素(COX/PGE)抑制阻止非类固醇抗炎药长期用于癌症 在普通人群中的迹象。我们的初步研究支持一种新的观点，即低剂量的舒林酸 通过选择miRNAs的非COX/PGE抑制机制来抑制CRC细胞的侵袭和转移。 有趣的是，首次发现外体miR-17-5p(Es-miR-17-5p)是关键的介体之一 被舒林酸靶向和调节以干预转移前的生态位形成。这些数据提供了 利用小剂量舒林酸预防和阻断结直肠癌转移的潜力的创新见解 进展，这还没有被专门研究。我们假设ES-miR-17-5p与 参与小剂量舒林酸延缓和潜在阻断结直肠癌的分子机制 转移。在我们的前提下，我们提出了三个具体目标，以证明LOW的一个新的迹象 舒林酸在控制转移性结直肠癌中的作用。在目标1中，我们将研究一种涉及ES-miR-17-5p的新机制 为了了解舒林酸对结直肠癌细胞运动的抑制作用；在目标2中，我们将确定其作用 利用动物模型研究ES-miR-17-5p介导舒林酸的体内抗转移活性；在目标3中，我们 将使用CRC样本评估miR-17-5p在预测肿瘤进展方面的临床应用。我们 期望我们的研究能够支持一种有效和安全的选择，以造福于患有晚期CRC和 最终改善退伍军人医疗保健。