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

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.