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Obesity is associated with risk of colorectal adenoma (CRA) and colorectal cancer. The signaling pathway activated by metformin (LKB1/AMPK/mTOR) is implicated in tumor suppression in ApcMin/+ mice via metformin-induced reduction in polyp burden, increased ratio of pAMPK/AMPK, decreased pmTOR/mTOR ratio, and decreased pS6Ser235/S6Ser235 ratio in polyps. We hypothesized that metformin would affect colorectal tissue S6Ser235 among obese patients with recent history of CRA. A phase IIa clinical biomarker trial was conducted via the U.S. National Cancer Institute-Chemoprevention Consortium. Nondiabetic, obese subjects (BMI ≥30) ages 35 to 80 with recent history of CRA were included. Subjects received 12 weeks of oral metformin 1,000 mg twice every day. Rectal mucosa biopsies were obtained at baseline and end-of-treatment (EOT) endoscopy. Tissue S6Ser235 and Ki-67 immunostaining were analyzed in a blinded fashion using Histo score (Hscore) analysis. Among 32 eligible subjects, the mean baseline BMI was 34.9. Comparing EOT to baseline tissue S6Ser235 by IHC, no significant differences were observed. Mean (SD) Hscore at baseline was 1.1 (0.57) and 1.1 (0.51) at EOT; median Hscore change was 0.034 (P = 0.77). Similarly, Ki-67 levels were unaffected by the intervention. The adverse events were consistent with metformin's known side-effect profile. Among obese patients with CRA, 12 weeks of oral metformin does not reduce rectal mucosa pS6 or Ki-67 levels. Further research is needed to determine what effects metformin has on the target tissue of origin as metformin continues to be pursued as a colorectal cancer chemopreventive agent.

Colorectal cancer progresses through multiple distinct stages that are potentially amenable to chemopreventative intervention. Epidermal growth factor receptor (EGFR) inhibitors are efficacious in advanced tumors including colorectal cancer. There is significant evidence that EGFR also plays important roles in colorectal cancer initiation, and that EGFR inhibitors block tumorigenesis. We performed a double-blind randomized clinical trial to test whether the EGFR inhibitor erlotinib given for up to 30 days had an acceptable safety and efficacy profile to reduce EGFR signaling biomarkers in colorectal aberrant crypt foci (ACF), a subset of which progress to colorectal cancer, and normal rectal tissue. A total of 45 patients were randomized to one of three erlotinib doses (25, 50, and 100 mg) with randomization stratified by nonsteroidal anti-inflammatory drug (NSAID) use. There were no unanticipated adverse events with erlotinib therapy. Erlotinib was detected in both normal rectal mucosa and ACFs. Colorectal ACF phosphorylated ERK (pERK), phosphorylated EGFR (pEGFR), and total EGFR signaling changes from baseline were modest and there was no dose response. Overall, this trial did not meet is primary efficacy endpoint. Colorectal EGFR signaling inhibition by erlotinib is therefore likely insufficient to merit further studies without additional prescreening stratification or potentially longer duration of use. Cancer Prev Res; 8(3); 222–30. ©2015 AACR.

Background: Despite advances in colorectal cancer (CRC) screening, early detection, and treatment, CRC remains the 2nd most common cancer cause of death in the U.S.. Obesity is increasing in incidence in the U.S., and has been implicated in colorectal adenoma (CRA) risk, risk of CRA recurrence, and risk of CRC. Obese patients with history of CRA are a high-risk group that may benefit from novel CRC prevention strategies. There is early evidence for reduced cancer mortality among metformin users. The signaling pathway activated by metformin (LKB1/AMPK/mTOR) is implicated in tumor suppression in ApcMin/+ mice, as evidenced by metformin-induced reduction in polyp burden, increased ratio of pAMPK/AMPk, decreased ratio of pmTOR/mTOR, and decreased ratio of pS6Ser235/S6Ser235 in polyp specimens. We hypothesized that metformin would affect colorectal tissue S6Ser235 similarly in humans, targeting obese patients with recent history of CRAs as a high-risk group. Methods: A phase IIa clinical biomarker trial was conducted across 3 clinical sites via the NCI-funded Southern California Chemoprevention Program. Eligible participants included non-diabetic, obese patients (BMI >30) with history of colorectal adenoma within the past 3 years, age ≥ 35 years and ≤ 80 years. All patients received an upward titration of metformin over 3 weeks to 1000mg po bid, which was continued until the end-of-study (EOS) at 12 weeks. Rectal mucosa biopsies were obtained at baseline (BL) and at time of EOS endoscopy. Tissue S6Ser235 immunostaining was analyzed in a blinded fashion by the study pathologist using Histo Score (HScore) analysis. A paired t-test was used to examine the effect of metformin on activated S6serine235 (i.e., the ratio of pS6serine235/ S6serine235). Results: 45 patients were consented to achieve 32 eligible subjects. 4 subjects were removed from study due to Adverse Events (1 SAE, unrelated). In order of frequency, the most common AEs were diarrhea, cramping, flatulence, nausea, stomach pain; 80% of participants had Grade 1 AE, 27% had grade 2 AE. Mean (SD) weight and body mass index at BL were 105.2 (17.42) kg and 34.9 (5.57) respectively. Weight did not significantly differ over the course of the study. Glucose levels at EOS did not significantly differ from BL. Vitamin B12 levels were significantly reduced at EOS vs. BL (-46.7 pg/mL, 95% CI -73.2 to -20.2). Comparing EOS to BL tissue S6Ser235 by IHC HScore analysis, no significant differences were observed. Mean (SD) Hscore at BL was 1.1 (0.57) and 1.1 (0.51) at EOS. Median HScore change was 0.032 (p=0.77). Conclusions: Among obese CRA patients, 12 weeks of oral metformin 1000mg twice daily does not reduce pS6 levels in the rectal mucosa. Other potential mechanisms of action have not yet been analyzed. Data from this clinical trial indicate that metformin can be used safely in a non-diabetic population. Further research is needed to determine what effects, if any, metformin has on the target tissue of origin (colorectum) relevant to colorectal carcinogenesis if metformin is to be pursued as a CRC chemopreventive agent. Citation Format: Jason A. Zell, Christine E. McLaren, Timothy R. Morgan, Michael J. Lawson, Sherif Rezk, Gregory C. Albers, Wen-Pin Chen, Joseph C. Carmichael, Luz Rodriguez, Eva Szabo, Leslie Ford, Michael Pollak, Frank L. Meyskens. A Phase IIa trial of metformin for colorectal cancer risk reduction among patients with a history of colorectal adenomas and elevated body mass index. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A21.

Colorectal cancer (CRC) progresses through multiple distinct stages that are potentially amenable to chemopreventative intervention. Epidermal Growth Factor Receptor (EGFR) inhibitors can shrink advanced tumors including CRC. There is significant evidence that EGFR also plays important roles in CRC initiation, and that EGFR inhibitors block tumorigenesis. We therefore performed a double-blind randomized trial (N=45) to test whether the EGFR inhibitor erlotinib (25mg, 50mg and 100mg doses) given for up to 28 days had an acceptable safety and efficacy profile to reduce EGFR signaling biomarkers in colorectal aberrant crypt foci (ACF), a subset of which progress to CRC, and normal rectal tissue. Participants were stratified by NSAID dose. Erlotinib was well tolerated and there were no unanticipated adverse events. Colorectal ACF and normal tissue EGFR signaling changes with erlotinib were modest and there was no clear dose response. However, individuals with high baseline EGFR signaling may potentially constitute a subset that could benefit from this strategy. Overall, our results support the safety of erlotinib in the chemoprevention setting, but efficacy in colorectal EGFR signaling inhibition is likely insufficient to merit further studies without additional pre-screening stratification. Citation Format: Steven Lipkin, Asmita Bhattacharya, Timothy Morgan, Jason Zell, Daniel Gillen, Vanessa Wong, Jinah Chung, Wen Pin Chen, Rachel Gonzalez, Frank Meyskens, Luz Rodriguez, Eva Szabo, Robert Carroll, Richard Benya. A phase IIa randomized, double-blind trial of erlotinib in inhibiting EGF receptor signaling in aberrant crypt foci of the colon. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr CN07-01.

Difluoromethyl ornithine (DFMO), an ornithine decarboxylase inhibitor, and sulindac reduced the occurrence of colorectal adenomas by 70% in a phase III randomized placebo controlled clinical trial. The goal of the current study was to compare adenoma location in the colorectum and biomarker expression by immunohistochemistry of formalin fixed paraffin embedded adenomas from treatment and placebo groups in the trial. To take into account the relationship between the locations in the colorectum of multiple adenoma that were removed from individual subjects, the generalized estimation equation (GEE) method was applied for all analyses. The decrease in the reappearance of metachronous adenomas was similar throughout the colorectum in subjects treated with DFMO and sulindac (P = 0.44). For TP53, Ki67, and c-MYC there were no significant differences in the estimated mean percent of cells staining positive between treated and untreated subjects (P>0.5 for all). For BCL-2, LC3B, CEA, sialy1-Tn, cleaved caspase 3 and apoptosis, the proportion of adenoma with expression levels 1+ to 3+ did not differ between subjects treated with DFMO plus sulindac versus those treated with double placebos. For hMSH2, hMSH6, hMLH1 and hPMS2, there was a loss of staining of a greater number of cells on average in adenomas from the control group compared to adenomas from the subjects treated with DFMO and sulindac. For hMSH2, this difference was statistically significant (P = 0.0004). This finding raises the possibility that DFMO and sulindac protect adenomas from loss of DNA mismatch repair protein expression and provides a rationale for further study of the possible role of DFMO and sulindac on DNA mismatch repair protein regulation and chemoprevention in patients at risk for colorectal carcinoma. In conclusion, DFMO decreases the occurrences of adenomas throughout the colorectum, including the right colon, and may have an effect on DNA mismatch repair enzyme expression. These findings provide further rationale for the use of DFMO as a chemopreventative agent for colorectal carcinoma. Citation Information: Cancer Prev Res 2011;4(10 Suppl):PR-01.

Background: The pharmacologic targeting of polyamines and prostaglandin E2 (PGE2) has proven efficacy for colorectal adenoma prevention. However, the contribution of these analytes as biomarkers of drug response has not been investigated. Methods: We analyzed the relationships between rectal mucosal levels of polyamines (spermidine, spermine, and putrescine) and PGE2, treatment, and risk of adenoma within the context of a phase IIb/III trial of combination difluoromethylornithine (DFMO) plus sulindac for the prevention of colorectal adenoma. Results: We detected no differences in the change in PGE2 levels between the two groups for any time points, but we show a statistically significant decrease in spermidine:spermine levels and in putrescine levels in the DFMO/sulindac group at 12 and 36 months compared to the placebo arm. When we asked whether or not change in polyamine or putrescine levels was associated with adenoma recurrence in the treatment arm only, we found no difference in the rate of metachronous events by change in polyamine or PGE2 levels in the treatment arm. We also found no evidence that polyamine or PGE2 levels were associated with risk of adenoma when we restricted the analysis to the placebo arm only. Of interest, we found that participants with low baseline spermidine:spermine levels who received DFMO/sulindac achieved a significantly greater benefit from treatment (RR = 0.15, 95% CI = 0.06 to 0.40) than those with high baseline spermidine:spermine receiving drug (RR = 0.50, 95% CI = 0.27 to 0.92). Conclusions: DFMO/sulindac significantly suppressed the production of rectal mucosal polyamines, but the magnitude of change was not predictive of response to intervention. This was likely due to the large effect of DFMO/sulindac on adenoma recurrence. We found no evidence in the placebo arm that baseline polyamine or PGE2 were associated with the risk of developing adenoma. The modulating effect of baseline spermidine:spermine levels on metachronous adenoma, in those individuals receiving the drug combination, provides evidence of differential agent-effectiveness by steady-state polyamine levels that should be investigated in future studies. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A29.