Kurzfassung

Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin (ASA) (< 100 mg/day) can inhibit colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin (MET) has also been associated with decreased colorectal cancer incidence and mortality in meta-analyses of epidemiological studies in diabetics. Recent studies have shown that ASA is an inhibitor of mTOR/S6K1 and an activator of AMPK, targeting regulators of...Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin (ASA) (< 100 mg/day) can inhibit colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin (MET) has also been associated with decreased colorectal cancer incidence and mortality in meta-analyses of epidemiological studies in diabetics. Recent studies have shown that ASA is an inhibitor of mTOR/S6K1 and an activator of AMPK, targeting regulators of intracellular energy
homeostasis and metabolism, and that the combination of ASA and MET, another AMPK activator and 6SK1 inhibitor, has a striking additive effect on AMPK activation and mTOR inhibition, with increased autophagy and decreased cell growth in CRC cell lines. The two agents have also been shown to act synergistically at low concentrations (1-5 mmol/L) to arrest pancreatic cancer cell lines by inhibiting the phosphorylation of mTOR, S6K, JAK2 and STAT3. While both drugs are being tested as single agents, their combination has not been tested in clinical trials. We propose a randomized, placebo-controlled, double blind, double dummy, 2x2 biomarker trial of ASA and MET to test the activity of either agent alone and the potential synergism of their combination on a set of surrogate biomarkers of colorectal carcinogenesis. After surgery and, if applicable, completion of adjuvant chemotherapy, 160 patients with stage I-III colon cancer will randomly be assigned in a four-arm trial to either ASA, 100 mg day, MET 850 mg bis in die, their combination, or placebo for one year. The primary endpoint biomarker is the change, defined as the difference between post- and pre-treatment in the immunoistochemical (IHC) expression of
nuclear factor kappa-B (NFκB), a key transcription factor in inflammation and colon carcinogenesis, in the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in two paired colonoscopies one year apart. Additional biomarkers will include: 1) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome wide gene expression arrays; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of several mutations and SNPs with treatment response by next generation sequencing of primary tumors; 4) the measurement of circulating IL-6, CRP and VEGF. These biomarkers have been selected to elucidate the impact of the interventions on molecular/cellular mechanisms in epithelial tissue or circulation that characterize risk of cancer recurrence and metastasis. Moreover, their modulation by the preventive interventions may provide important clues for a subsequent phase III adjuvant trial aimed at preventing second primary cancer, delaying recurrence and improving prognosis in patients with CRC.» weiterlesen» einklappen