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Assessment of Direct Biomarkers of Aspirin Action to Develop a Precision Chemoprevention Therapy of Colorectal Cancer

ABSTRACT: Acetylsalicylic acid (ASA) seems the ideal colorectal cancer (CRC) chemoprevention agent. Several ongoing trials are testing the effect of ASA as co-therapy in CRC. The mechanisms of action, the appropriate dose and the ideal target population are unknown. The investigators have demonstrated that doses of 100 mg of ASA induce direct and partial but persistent acetylation of the cyclooxygenase (COX) isoenzyme COX-1 in the normal colorectal mucosa. The primary objective is to perform a study of aspirin by using a proteomic assay for comparing platelet COX-1 and CRC mucosal COX-1 after different doses of ASA. Secondary objectives are: the measurement of prostaglandin E2 (PGE2) and phosphorylated S6 protein (p-S6) levels in CRC mucosa, the assessment of indirect biomarker of aspirin action (serum thromboxane B2 (TXB2) and urinary levels of 11-dehydro-TXB2 (TX-M)), the evaluation of systemic biomarkers of inflammatory/tumorigenic COX-2 by assessing urinary levels of major metabolite of PGE2 (PGE-M). Methods: Phase II randomized clinical trial in 60 patients with newly diagnosed CRC in 3 groups of 20 patients receiving 100 or 300 mg/day, or 100 mg/12 hours of enteric-coated ASA for 3±1 weeks, prior to definitive treatment by surgery. Main outcome: Acetylation of COX-1 and COX-2. Eicosanoid levels in target organs. Expected results: Evidence for the current uncertainty about the mechanisms of action and the dose required to obtain the best chemopreventive effect with ASA in CRC. Confirm acetylation of COX as a key biomarker of efficacy with ASA.

DISEASE(S): Colorectal Cancer With A Recent Confirmed Diagnosis (less Than 48h),Colorectal Cancer,Colorectal Cancer With A Recent Confirmed Diagnosis (less Than 48h),Colorectal Neoplasms,Cáncer Colorrectal Con Un Diagnóstico Confirmado Reciente (menos De 48h)

PROVIDER: 2306166 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Colorectal cancer (CRC) remains the leading cause of cancer-related death in the world. Aspirin (ASA) and curcumin (CUR) are widely investigated chemopreventive candidates for CRC. However, the precise mechanisms of their action and their combinatorial effects have not been evaluated. The purpose of the present study was to determine the effect of ASA, CUR, and their combination in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-accelerated colorectal cancer (CAC). We also aimed to characterize the differential gene expression profiles in AOM/DSS-induced tumors as well as in tumors modulated by ASA and CUR using RNA-seq. Diets supplemented with 0.02% ASA, 2% CUR or 0.01% ASA + 1% CUR were given to mice from 1 week prior to the AOM injection until the experiment was terminated 22 weeks after AOM initiation. Our results showed that CUR had a superior inhibitory effect in colon tumorigenesis compared to that of ASA. The combination of ASA and CUR at a lower dose exhibited similar efficacy to that of a higher dose of CUR at 2%. RNA isolated from colonic tissue from the control group and from tumor samples from the experimental groups was subjected to RNA-seq. Transcriptomic analysis suggested that the low-dose combination of ASA and CUR modulated larger gene sets than the single treatment. These differentially expressed genes were situated in several canonical pathways important in the inflammatory network and liver metastasis in CAC. We identified a small subset of genes as potential molecular targets involved in the preventive action of the combination of ASA and CUR. Taken together, the current results provide the first evidence in support of the chemopreventive effect of a low-dose combination of ASA and CUR in CAC. Moreover, the transcriptional profile obtained in our study may provide a framework for identifying the mechanisms underlying the carcinogenesis process from normal colonic tissue to tumor development as well as the cancer inhibitory effects and potential molecular targets of ASA and CUR.

Dataset Information

Assessment of Direct Biomarkers of Aspirin Action to Develop a Precision Chemoprevention Therapy of Colorectal Cancer

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