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Principal Investigator: Yaguang Xi
Organization: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
Fiscal Year: 2024
Funding agency: Veterans Affairs
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.
Terms: <Acetylsalicylic Acid><Address><Animal Model><Animal Models and Related Studies><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Arachidonic Acid Cyclooxygenase><Armed Forces Personnel><Aspirin><Biogenesis><Blood Plasma><Blood Sample><Blood specimen><Body Tissues><CRC prevention><Cancer Cause><Cancer Control><Cancer Control Science><Cancer Drug><Cancer Etiology><Cancer Intervention><Cancer Patient><Cancers><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Locomotion><Cell Migration><Cell Movement><Cellular Migration><Cellular Motility><Cessation of life><Characteristics><Clinic><Clinical><Clinical Trials><Colon or Rectum><Colorectal><Colorectal Cancer><Cyclo-Oxygenase><Cyclooxygenase><Data><Death><Development><Disease><Disorder><Distant><Distant Cancer><Distant Metastasis><Dose><Drugs><Experimental Animal Model><FDA approved><Familial Adenomatous Polyposis Syndrome><Familial Polyposis Syndrome><Fatty Acid Cyclo-Oxygenase><Forms Controls><Future><General Population><General Public><Generic Drugs><Genes><Healthcare><Heart Vascular><Human><Hydroperoxide Cyclase><Incidence><Increase lifespan><Individual><Invaded><Lead><Lesion><Liver><Lung><Lung Respiratory System><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mediating><Mediator><Medical center><Medication><Meta-Analysis><Metastasis><Metastasize><Metastatic Adenocarcinoma><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Micro RNA><MicroRNAs><Military><Military Personnel><Modeling><Modern Man><Molecular><Murine><Mus><NSAIDs><Neoplasm Metastasis><Neoplastic Disease Chemotherapeutic Agents><Non-Steroidal Anti-Inflammatory Agents><Non-proprietary Drugs><Nonproprietary Drugs><Oncogenesis><Organ><Origin of Life><PDX model><PGH Synthase><PGH2 Synthetase><PK/PD><Patient derived xenograft><Patients><Pb element><Pharmaceutical Preparations><Physicians><Plasma><Plasma Serum><Polyps><Prostaglandin Cyclo-Oxygenase><Prostaglandin Cyclooxygenase><Prostaglandin Endoperoxide Synthetase><Prostaglandin G-H Synthase><Prostaglandin H Synthase><Prostaglandin H2 Synthetase><Prostaglandin Inhibition><Prostaglandin Synthase><Prostaglandin Synthetase><Prostaglandin-Endoperoxide Synthase><RNA Seq><RNA sequencing><RNAseq><Randomized Controlled Clinical Trials><Regulation><Reporting><Research Resources><Research Specimen><Resources><Reticuloendothelial System, Serum, Plasma><Risk><Role><Safety><Sampling><Secondary Neoplasm><Secondary Tumor><Specimen><Sulindac><Survival Rate><System><Therapeutic><Time><Tissue Arrays><Tissue Chip><Tissue Microarray><Tissues><Toxic effect><Toxicities><Treatment Efficacy><Tumor Suppressor Proteins><Tumor-Derived><Tumor-Specific Treatment Agents><United States><United States Department of Veterans Affairs><United States Veterans Administration><Veterans><Veterans Administration><Veterans Affairs><Xenograft Model><adenoma><advanced disease><advanced illness><anti-cancer drug><biomarker validation><cancer cell><cancer chemoprevention><cancer metastasis><cancer progression><cell motility><circulatory system><colon cancer patients><colorectal cancer metastasis><colorectal cancer patients><colorectal cancer prevention><colorectal cancer progression><colorectum><death risk><developmental><drug/agent><elongating the lifespan><exosome><extend life span><extend lifespan><familial adenomatous polyposis><familial polyposis><health care><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><implantation><improved><in vivo><innovate><innovation><innovative><insight><interest><intervention efficacy><lifespan extension><malignancy><marker validation><metastatic colo-rectal><metastatic colo-rectal cancer><metastatic colo-rectal carcinoma><metastatic colon cancer><metastatic colorectal><metastatic colorectal cancer><metastatic colorectal carcinoma><miRNA><miRNAs><military population><model of animal><mortality risk><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic progression><non-steroidal anti-inflammatory drugs><novel><patient derived xenograft model><peripheral blood><pharmacokinetics and pharmacodynamics><pre-clinical study><precancer><precancerous><preclinical study><premalignant><pressure><prevent><prevent colorectal cancer><preventing><pulmonary><randomized control clinical trial><social role><success><systemic toxicity><therapeutic efficacy><therapy efficacy><transcriptome sequencing><transcriptomic sequencing><tumor><tumor cell metastasis><tumor progression><tumor suppressor><tumorigenesis><xenograft transplant model><xenotransplant model>