Gary Della'Zanna

Randomized phase II trial of sulindac, atorvastatin, and prebiotic dietary fiber for colorectal cancer chemoprevention.

Sulindac, atorvastatin, or prebiotic dietary fiber may reduce colorectal cancer (CRC) risk. However, clinical trial data are currently limited. We conducted a randomized, phase II chemoprevention trial involving subjects 40 years or older, with previously resected colon cancer or multiple/advanced colorectal adenomas. Magnification chromoendoscopy (MCE) was performed to identify and characterize rectal aberrant crypt foci (ACF); eligibility criteria required five or more rectal ACFs at baseline. Intervention assignments were as follows: (a) atorvastatin 20 mg qd; (b) sulindac 150 mg bid; (c) oligofructose-enriched inulin (as ORAFTI®Synergy1) 6 gm bid; or (d) control (maltodextrin) 6 gm bid, for 6 months. Percent change in rectal ACF number (%ΔACF) within arm was the primary endpoint. Secondary endpoints included changes in proliferation (Ki67) and apoptosis (caspase-3), as measured from normal mucosa biopsy samples. Among 85 eligible randomized subjects, 76 (86%) completed the trial per protocol. The median (range) of rectal ACF was 9 (5–34) and 8 (0–37) at baseline and postintervention, respectively. The median (SD) for %ΔACF was 5.6 (−69% to 143%), −18.6 (−83% to 160%), −3.6 (−88% to 83%), and −10.0 (−100% to 117%) in the atorvastatin, sulindac, ORAFTI®Synergy1 and control arms, respectively. Neither within-arm (P = 0.12–0.59) nor between-arm (P = 0.30–0.92) comparisons of %ΔACF were statistically significant. The active and control interventions also seemed to have similar effects on mucosal proliferation and apoptosis (P > 0.05 for each comparison). Data from this multicenter, phase II trial do not provide convincing evidence of CRC risk reduction from 6-month interventions with atorvastatin, sulindac, or ORAFTI®Synergy1, although statistical power was limited by the relatively small sample size. Cancer Prev Res; 4(2); 259–69. ©2011 AACR.

A Combination of Esomeprazole and Aspirin Reduces Tissue Concentrations of Prostaglandin E2 in Patients With Barrett's Esophagus

UNLABELLED BACKGROUND& AIMS: Proton pump inhibitors and nonsteroidal anti-inflammatory drugs might prevent esophageal adenocarcinoma in patients with Barretts esophagus (BE), but there are limited data from clinical trials to support this concept. We conducted a randomized, double-blind, placebo-controlled, phase 2 trial to assess the effects of the combination of aspirin (3 different doses) and esomeprazole on tissue concentrations of prostaglandin (PG) E(2) in patients with BE with no dysplasia or low-grade dysplasia. METHODS Participants were recruited through the multicenter Cancer Prevention Network and randomly assigned to groups that were given 40 mg esomeprazole twice daily in combination with an aspirin placebo once daily (arm A; n = 30), with 81 mg aspirin once daily (arm B; n = 47), or with 325 mg aspirin once daily (arm C; n = 45) for 28 days. We collected esophageal biopsy specimens before and after the intervention period to determine the absolute change in mean concentration of PGE(2) (the primary end point). RESULTS Based on data from 114 patients, baseline characteristics were similar among groups. The absolute mean tissue concentration of PGE(2) was reduced by 67.6 ± 229.68 pg/mL in arm A, 123.9 ± 284.0 pg/mL in arm B (P = .10 vs arm A), and 174.9 ± 263.62 pg/mL in arm C (P = .02 vs arm A). CONCLUSIONS In combination with esomeprazole, short-term administration of higher doses of aspirin, but not lower doses or no aspirin, significantly reduced tissue concentrations of PGE(2) in patients with BE with either no dysplasia or low-grade dysplasia. These data support further evaluation of higher doses of aspirin and esomeprazole to prevent esophageal adenocarcinoma in these patients. Clinical trial registration number NCT00474903.

Spectral biomarkers for chemoprevention of colonic neoplasia: a placebo-controlled double-blinded trial with aspirin

Objective A major impediment to translating chemoprevention to clinical practice has been lack of intermediate biomarkers. We previously reported that rectal interrogation with low-coherence enhanced backscattering spectroscopy (LEBS) detected microarchitectural manifestations of field carcinogenesis. We now wanted to ascertain if reversion of two LEBS markers spectral slope (SPEC) and fractal dimension (FRAC) could serve as a marker for chemopreventive efficacy. Design We conducted a multicentre, prospective, randomised, double-blind placebo-controlled, clinical trial in subjects with a history of colonic neoplasia who manifested altered SPEC/FRAC in histologically normal colonic mucosa. Subjects (n=79) were randomised to 325 mg aspirin or placebo. The primary endpoint changed in FRAC and SPEC spectral markers after 3 months. Mucosal levels of prostaglandin E2 (PGE2) and UDP-glucuronosyltransferase (UGT)1A6 genotypes were planned secondary endpoints. Results At 3 months, the aspirin group manifested alterations in SPEC (48.9%, p=0.055) and FRAC (55.4%, p=0.200) with the direction towards non-neoplastic status. As a measure of aspirins pharmacological efficacy, we assessed changes in rectal PGE2 levels and noted that it correlated with SPEC and FRAC alterations (R=−0.55, p=0.01 and R=0.57, p=0.009, respectively) whereas there was no significant correlation in placebo specimens. While UGT1A6 subgroup analysis did not achieve statistical significance, the changes in SPEC and FRAC to a less neoplastic direction occurred only in the variant consonant with epidemiological evidence of chemoprevention. Conclusions We provide the first proof of concept, albeit somewhat underpowered, that spectral markers reversion mirrors antineoplastic efficacy providing a potential modality for titration of agent type/dose to optimise chemopreventive strategies in clinical practice. Trial Number NCT00468910

Bioactivity of Oral Linaclotide in Human Colorectum for Cancer Chemoprevention

Guanylate cyclase C (GUCY2C) is a tumor-suppressing receptor silenced by loss of expression of its luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Linaclotide is an FDA-approved oral GUCY2C agonist formulated for gastric release, inducing fluid secretion into the small bowel to treat chronic idiopathic constipation. The ability of oral linaclotide to induce a pharmacodynamic response in epithelial cells of the colorectum in humans remains undefined. Here, we demonstrate that administration of 0.87 mg of oral linaclotide daily for 7 days to healthy volunteers, after oral colon preparation with polyethylene glycol solution (MoviPrep), activates GUCY2C, resulting in accumulation of its product cyclic (c)GMP in epithelial cells of the cecum, transverse colon, and distal rectum. GUCY2C activation by oral linaclotide was associated with homeostatic signaling, including phosphorylation of vasodilator-stimulated phosphoprotein and inhibition of proliferation quantified by reduced Ki67-positive epithelial cells. In the absence of the complete oral colonoscopy preparation, linaclotide did not alter cGMP production in epithelial cells of the colorectum, demonstrating that there was an effect related to the laxative preparation. These data show that the current FDA-approved formulation of oral linaclotide developed for small-bowel delivery to treat chronic idiopathic constipation is inadequate for reliably regulating GUCY2C in the colorectum to prevent tumorigenesis. The study results highlight the importance of developing a novel GUCY2C agonist formulated for release and activity targeted to the large intestine for colorectal cancer prevention. Cancer Prev Res; 10(6); 345–54. ©2017 AACR.

Clinical Study of Ursodeoxycholic Acid in Barrett's Esophagus Patients

Prior research strongly implicates gastric acid and bile acids, two major components of the gastroesophageal refluxate, in the development of Barretts esophagus and its pathogenesis. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, has been shown to protect esophageal cells against oxidative stress induced by cytotoxic bile acids. We conducted a pilot clinical study to evaluate the clinical activity of UDCA in patients with Barretts esophagus. Twenty-nine patients with Barretts esophagus received UDCA treatment at a daily dose of 13 to 15 mg/kg/day for 6 months. The clinical activity of UDCA was assessed by evaluating changes in gastric bile acid composition and markers of oxidative DNA damage (8-hydroxydeoxyguanosine), cell proliferation (Ki67), and apoptosis (cleaved caspase-3) in Barretts esophagus epithelium. The bile acid concentrations in gastric fluid were measured by liquid chromatography/mass spectrometry. At baseline, UDCA (sum of unchanged and glycine/taurine conjugates) accounted for 18.2% of total gastric bile acids. After UDCA intervention, UDCA increased significantly to account for 93.4% of total gastric bile acids (P < 0.0001). The expression of markers of oxidative DNA damage, cell proliferation, and apoptosis was assessed in the Barretts esophagus biopsies by IHC. The selected tissue biomarkers were unchanged after 6 months of UDCA intervention. We conclude that high-dose UDCA supplementation for 6 months resulted in favorable changes in gastric bile acid composition but did not modulate selected markers of oxidative DNA damage, cell proliferation, and apoptosis in the Barretts esophagus epithelium. Cancer Prev Res; 9(7); 528–33. ©2016 AACR. See related article by Brian J. Reid, p. 512

548 Correlation of Spectral Signatures With Rectal Prostaglandin E2 Levels As Biomarkers for Aspirin Chemoprevention of Colon Carcinogenesis: Results From a Placebo-Controlled Double Blinded Phase 2B Trial

G A A b st ra ct s had ≥1 adenoma at repeat colonoscopy. Compared to no-therapy, patients exposed to metformin-only had a lower risk of adenoma recurrence irrespective of exam indication (screening, n= 622, HR=0.69 CI: 0.51-0.93; surveillance n= 1308, HR=0.88 CI: 0.71-1.08; diagnostic n=667, HR=0.58 CI: 0.41-0.84). However, the association was not statistically significant in patients who underwent surveillance exams. Conclusion: Metformin use was associated with a reduced risk of recurrent or new primary adenoma after polypectomy. If confirmed in further studies in other subgroups of patients and in randomized trials, metformin could have an important role in the secondary prevention of colorectal adenomas.

Mo1161 Phase 2B Randomized Placebo-Controlled Spectral Markers As Biomarkers for Colonic Chemoprevention With Aspirin: Correlation With Rectal Apoptosis but Not Proliferation

BACKGROUND AND AIM: In the early stages of tumorigenesis, transforming growth factor (TGF)-β1-driven signaling provides tumor-suppressive action. TGF-β1 activity is inhibited by SMAD7, a protein that binds to TGFβ receptor and prevents TGF-β1-induced signal transduction. Forced expression of SMAD7 in cancer cells differently regulates tumorigenesis depending on the cell context analyzed, and preliminary evidence suggests that amplification of SMAD7 associates with a significantly worse prognosis in patients with colorectal cancer (CRC). In this study we evaluated the role of SMAD7 in the process of colon carcinogenesis. METHODS: SMAD7 expression was evaluated in human CRC samples, CRC cell lines (i.e. HCT-116, DLD-1, HT-29 and HT-115) and normal colonic epithelial cells by immunohistochemistry and Western blotting. HCT-116 and DLD-1 cells were transfected with a specific oligonucleotide antisense (GED-0301) or control sense, and cell proliferation, cell cycle, caspase-3 activation and apoptosis were then evaluated by flow-cytometry. Expression of cell cycle-related proteins (e.g., CDK2, CDC25A, cyclin D1) was assessed byWestern blotting. To evaluate the effect of SMAD7 knock-down on CRC growth in vivo, xenografts were induced in Rag1-deficient mice by subcutaneous injection of HCT-116 cells and mice were treated either with SMAD7 sense or GED-0301. RESULTS: High SMAD7 was seen in CRC samples as compared to matched normal, adjacent, colonic samples. Consistently, SMAD7 was highly expressed in several CRC cell lines but not in normal colonic epithelial cells. Transfection of HCT-116 and DLD-1 cells with GED-0301 down-regulated SMAD7 and inhibited cell growth. Cell cycle analysis revealed that silencing of SMAD7 with GED-0301 induced cells to accumulate in S phase and this effect was associated with a sustained phosphorylation of CDK2 and decreased expression of CDC25A and cyclin D1. Moreover, time-course studies revealed that GED-0301-mediated cell cycle arrest was followed by caspase-dependent induction of CRC cell apoptosis. Finally, in vivo studies showed that daily intra-peritoneal administration of GED-0301 markedly inhibited the development of HCT-116-derived xenografts. CONCLUSIONS: SMAD7 knock-down causes accumulation of CRC cells in S phase thereby promoting cell growth arrest and apoptosis. Data suggest that SMAD7 could be a promising molecular target for pharmacological intervention in CRC patients.

Abstract A67: Phase IIA trial testing erlotinib as an intervention against intraductal papillary mucinous neoplasms

Intraductal papillary mucinous neoplasms (IPMNs) account for about 7% of clinically diagnosed pancreatic neoplasm and up to 50% of all incidentally detected pancreatic cysts. Described by Oshi et al in 1982, the incidence of these mucin-producing epithelial tumors of the exocrine pancreas has been increasing. Furthermore, IPMNs are thought to be direct precursors of pancreatic ductal carcinoma (PDA), which is among the most lethal human cancers. Many of the IPMNs are detected occur in nonsurgical candidates. Those surgically resected, a significant proportion develops PDA in the pancreatic remnant and die of disseminated disease. There is currently no chemotherapy specifically approved for treating IPMNs. Erlotinib (Tarceva, OSI-774) is an anti epidermal growth factor receptor (EGFR) orally active antitumor agent for treatment of solid tumors that is used in combination with chemotherapy to treat pancreatic adenocarcinoma. A single arm, presurgical phase IIa trial using 100mg erlotinib in IPMNs patients (7-28 days prior to surgery) was conducted. Pre and post-erlotinib IPMN tissues were compared for a reduction in the EGF regulated biomarker Mucin 5AC (MUC 5AC) as the primary outcome. Secondary outcomes included clinical regression of IPMNs and quantification of the concentration of erlotinib in pancreatic tissue. Six IPMN patients were enrolled and pancreatic surgical specimens consistently showed decreased MUC5AC with erlotinib treatment. Additionally, one patient had a clinical complete response by CT criteria. No unanticipated safety issues were observed in trial participants. Overall, these preliminary results suggest erlotinib and other EGFR antagonists should be examined further for anti-IPMN activity. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A67.