MicroRNA, a new player for the NSAID sulindac to prevent colon cancer progression

描述(申请人提供)：根据美国癌症协会最新的癌症统计报告，结直肠癌仍然是美国癌症死亡的主要原因。非甾体抗炎药(NSAIDs)已被证明能显著降低结直肠癌的发病率和死亡风险，但环氧合酶(COX)抑制和生理上重要的前列腺素的抑制导致的副作用限制了它们用于化学预防的长期使用。据报道，非甾体抗炎药舒林酸对家族性腺瘤性息肉病患者的癌前病变有很高的治疗效果，并在临床前动物模型中显示出良好的抗癌活性。我们的初步数据显示，舒林酸的硫代谢物(SS)能够有效地抑制人结肠肿瘤细胞的侵袭，这表明该药物可能抑制与转移相关的生物学过程。其机制似乎涉及抑制转录因子NF-kB，以抑制致癌microRNA(MiRNA)簇miR-17-92，并诱导在调节肿瘤细胞黏附和转移中发挥重要作用的肿瘤抑制蛋白震颤(QKI)。我们的结果表明，这一机制可能不需要COX抑制，因为非COX抑制衍生物舒林酸硫酰胺(SSA)可以明显地诱导QKI并抑制结肠肿瘤细胞的侵袭。SSA的药效明显强于SS，因为它具有良好的口服生物利用度和独特的组织分布模式，可在肺和肝脏这两个主要转移部位实现高浓度 死于结直肠癌。我们假设舒林酸抑制肿瘤侵袭的机制与其COX抑制活性无关；miR-17-92/QKI轴解释或部分负责这一作用。本研究的目的是：1)研究miR-17-92/QKI轴在介导Slindac体外抗侵袭活性中的作用；2)研究miR-17-92/QKI轴在介导舒林酸体内抗转移活性中的作用。这项申请是应PA-12-214的要求提交的，将涉及两个研究目标：“确定非编码RNA(NcRNAs)靶向的、易导致癌症发生或进展的分子途径”和“确定干扰致癌ncRNAs的处理、靶点选择或相关途径是否能阻止癌症进展”。拟议中的研究有可能通过以下方面影响人类健康：1)支持使用FDA批准的仿制药舒林酸预防结直肠癌患者的转移进展；2)评估舒林酸的一种新的非COX抑制剂，以加速其临床前开发；以及3)为发现临床试验的新生物标记物提供对ncRNA靶点的洞察。

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. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to significantly reduce the incidence and risk of death from colorectal cancer, but adverse side effects resulting from cyclooxygenase (COX) inhibition and suppression of physiologically important prostaglandins limit their long-term use for chemoprevention. The NSAID, sulindac has been reported to be highly effective for the treatment of precancerous adenomas in individuals with familial adenomatous polyposis and has shown promising anticancer activity in preclinical animal models. Our preliminary data show that the sulfide metabolite of sulindac (SS) can potently inhibit the invasion of human colon tumor cells, which suggest that this drug may inhibit biological processes associated with metastasis. The mechanism appears to involve the inhibition of the transcription factor, NF-kB to suppress an oncogenic microRNA (miRNA) cluster, miR-17- 92, and induce a tumor suppressor protein, quaking (QKI) that plays an important role in regulating tumor cell adhesion and metastasis. Our results suggest that this mechanism might not require COX inhibition because a non-COX inhibitory derivative, sulindac sulfide amide (SSA) can apparently induce QKI and inhibit colon tumor cell invasion. SSA is appreciably more potent than SS as it has good oral bioavailability with a unique tissue distribution pattern to achieve high concentrations in lung and liver, two main sites of metastasis from colorectal cancer. We hypothesize that the mechanism by which sulindac inhibits tumor invasion is unrelated to its COX inhibitory activity; and the miR-17-92/QKI axis accounts or is partially responsible for this action. The proposed aims are to: 1) study the role of the miR-17-92/QKI axis in mediating anti-invasive activity of slindac in vitro; and 2) study the role of the miR-17-92/QKI axis in mediating anti-metastatic activity of sulindac in vivo. This application is being submitted in response to PA-12-214 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) supporting the use of an FDA approved generic drug, sulindac, for the prevention of metastatic progression in patients with colorectal cancer; 2) evaluating a novel non-COX inhibitory of sulindac to accelerate its preclinical development; and 3) providing insight into ncRNA targets for the discovery of new biomarkers for clinical trials.