title: Oncogenic targets Mmp7, S100a9, Nppb and Aldh1a3 from transcriptome profiling of FAP and Pirc adenomas are downregulated in response to tumor suppression by Clotam.
abstract: Intervention strategies in familial adenomatous polyposis (FAP) patients and other high-risk colorectal cancer (CRC) populations have highlighted a critical need for endoscopy combined with safe and effective preventive agents. We performed transcriptome profiling of colorectal adenomas from FAP patients and the polyposis in rat colon (Pirc) preclinical model, and prioritized molecular targets for prevention studies in vivo. At clinically relevant doses in the Pirc model, the drug Clotam (tolfenamic acid, TA) was highly effective at suppressing tumorigenesis both in the colon and in the small intestine, when administered alone or in combination with Sulindac. Cell proliferation in the colonic crypts was reduced significantly by TA, coincident with increased cleaved caspase-3 and decreased Survivin, β-catenin, cyclin D1 and matrix metalloproteinase 7. From the list of differentially expressed genes prioritized by transcriptome profiling, Mmp7, S100a9, Nppb and Aldh1a3 were defined as key oncogene candidates downregulated in colon tumors after TA treatment. Monthly colonoscopies revealed the rapid onset of tumor suppression by TA in the Pirc model, and the temporal changes in Mmp7, S100a9, Nppb and Aldh1a3, highlighting their value as potential early biomarkers for prevention in the clinical setting. We conclude that TA, an "old drug" repurposed from migraine, offers an exciting new therapeutic avenue in FAP and other high-risk CRC patient populations.
authors.affiliation: Center for Epigenetics & Disease Prevention, Texas A&M University Institute of Biosciences & Technology, Houston, TX.|University of Pittsburg Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Furkan U
authors.initials: FU
authors.lastname: Ertem
authors.affiliation: Center for Epigenetics & Disease Prevention, Texas A&M University Institute of Biosciences & Technology, Houston, TX.
authors.forename: Wenqian
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Kyle
authors.initials: K
authors.lastname: Chang
authors.affiliation: Center for Epigenetics & Disease Prevention, Texas A&M University Institute of Biosciences & Technology, Houston, TX.
authors.forename: Wan
authors.initials: W
authors.lastname: Mohaiza Dashwood
authors.affiliation: Center for Epigenetics & Disease Prevention, Texas A&M University Institute of Biosciences & Technology, Houston, TX.
authors.forename: Praveen
authors.initials: P
authors.lastname: Rajendran
authors.affiliation: Center for Epigenetics & Disease Prevention, Texas A&M University Institute of Biosciences & Technology, Houston, TX.
authors.forename: Deqiang
authors.initials: D
authors.lastname: Sun
authors.affiliation: Center for Epigenetics & Disease Prevention, Texas A&M University Institute of Biosciences & Technology, Houston, TX.|Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Ala
authors.initials: A
authors.lastname: Abudayyeh
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Vilar
authors.affiliation: Center for Epigenetics & Disease Prevention, Texas A&M University Institute of Biosciences & Technology, Houston, TX.|Division of Medical Oncology, Duke University Medical Center, Durham, NC.
authors.forename: Maen
authors.initials: M
authors.lastname: Abdelrahim
authors.affiliation: Center for Epigenetics & Disease Prevention, Texas A&M University Institute of Biosciences & Technology, Houston, TX.|Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX.|Department of Nutrition and Food Science, Texas A&M University, College Station, TX.|Department of Molecular and Cellular Medicine, Texas A&M College of Medicine, College Station, TX.
authors.forename: Roderick H
authors.initials: RH
authors.lastname: Dashwood
mesh_terms: D000236:Adenoma / Q000188:drug therapy* / Q000235:genetics; D011125:Adenomatous Polyposis Coli / Q000188:drug therapy* / Q000235:genetics; D000445:Aldehyde Oxidoreductases / Q000235:genetics*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D040502:Calgranulin B / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics; D053148:Caspase 3 / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics; D051381:Rats; D051176:beta Catenin / Q000235:genetics; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: D014408:Biomarkers, Tumor; D040502:Calgranulin B; D051176:beta Catenin; D062367:ortho-Aminobenzoates; D019938:Cyclin D1; C009500:tolfenamic acid; D000445:Aldehyde Oxidoreductases; D053148:Caspase 3; D020783:Matrix Metalloproteinase 7
keywords: colorectal cancer; polyposis in rat colon; prevention; tolfenamic acid; β-catenin/Tcf