L.M. Rodriguez

A Phase II Randomized, Controlled Trial of S-Adenosylmethionine in Reducing Serum α-Fetoprotein in Patients with Hepatitis C Cirrhosis and Elevated AFP

In animal models of hepatocellular carcinoma (HCC), deficiency of S-adenosylmethionine (SAMe) increased the risk of HCC whereas administration of SAMe reduced HCC. The aim of this trial was to determine whether oral SAMe administration to patients with hepatitis C cirrhosis would decrease serum α-fetoprotein (AFP) level, a biomarker of HCC risk in hepatitis C. This was a prospective, randomized, placebo-controlled, double-blind trial of SAMe, up to 2.4 g/d, for 24 weeks as compared with placebo among subjects with hepatitis C cirrhosis and a mildly elevated serum AFP. Primary outcome was change in AFP between baseline and week 24. Secondary outcomes included changes in routine tests of liver function and injury, other biomarkers of HCC risk, SAMe metabolites, markers of oxidative stress, and quality of life. One hundred ten subjects were randomized and 87 (44 SAMe and 43 placebo) completed treatment. There was no difference in the change in AFP during 24 weeks among subjects receiving SAMe as compared with placebo. Changes in markers of liver function, liver injury, and hepatitis C viral level were not significantly different between groups. Similarly, SAMe did not change markers of oxidative stress or serum glutathione level. SAMe blood level increased significantly among subjects receiving SAMe. Changes in quality of life did not differ between groups. Overall, this trial did not find that SAMe treatment improved serum AFP in subjects with advanced hepatitis C cirrhosis and a mildly elevated AFP. SAMe did not improve tests of liver function or injury or markers of oxidative stress or antioxidant potential. Cancer Prev Res; 8(9); 864–72. ©2015 AACR.

Phase IIA trial testing erlotinib as an intervention against intraductal pancreatic mucinous neoplasms.

Intraductal papillary mucinous neoplasms (IPMN) are a distinct type of precursor lesions that cause about 5% of pancreatic adenocarcinoma (1, 2). Four-year survival rates of 40% to 75% are reported (3–7). There is currently no chemotherapy specifically approved for treating IPMNs. The number of IPMN cases has significantly increased over the last decade (8). Cancer Prev Res; 4(4); 512–3. ©2011 AACR.

Hereditary Colorectal Cancer and Polyposis Syndromes

Colorectal cancer (CRC) is the second leading cause of death in the United States, with approximately 10–30 % of patients having a positive family history. Lynch syndrome is the most common inherited CRC accounting for approximately 5–10 % of all CRC cases. Familial adenomatous polyposis (FAP) is the next common, accounting for approximately 1 % of all CRC cases. Other polyposis syndromes include attenuated FAP (aFAP), MYH-associated polyposis (MAP), Peutz–Jeghers syndrome (PJS), and juvenile polyposis syndrome (JPS). Each of these polyposis syndromes confers with it a higher lifetime risk of development of CRC due to their unique genetic mutations, necessitating early surveillance protocols and possible prophylactic surgical intervention. Extracolonic manifestations and cancer risks are also increased, emphasizing vigilance and early recognition of these anomalies. Preclinical trials have shown clear benefit in NSAIDS and COX inhibitors to exert their effects against all clinical stages of colorectal neoplasia. However, trials for deducing the specific aspects of adenoma reduction are still ongoing, especially in high-risk individuals with FAP and Lynch syndrome.

A phase IIa randomized, double-blind trial of erlotinib in inhibiting epidermal growth factor receptor signaling in aberrant crypt foci of the colorectum.

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.

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.

Abstract 3247: SAMe versus placebo for the reduction of serum AFP in patients with hepatitis C cirrhosis and moderately elevated AFP: A randomized, placebo-controlled, double-blind phase II trial

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAnnBackground: Hepatocellular carcinoma (HCC) is a common complication of hepatitis C virus related cirrhosis (HCV-C). Alpha-fetoprotein (AFP) has been proposed as a biomarker of HCC risk. S-adenosylmethionine (SAMe) is a food supplement that has an excellent safety profile. The use of SAMe as a chemopreventive is based on abnormalities in methionine cycle (with decreased SAMe levels) in patients with cirrhosis, increased risk of HCC in experimental animals deprived of SAMe, and the prevention of liver cancer by SAMe administration in animal models of chemically-induced HCC.nnMethods: This was a prospective, randomized, placebo-controlled, double-blind phase IIb trial to determine if SAMe (up to 2.4 grams/day) for 24 weeks reduced serum AFP levels in patients with HCV-C. Inclusion criteria: lab evidence of HCV-C (platelet count 15), or history of, or mass suspicious for HCC. Primary outcome was decline in AFP between week 0 and 24. Secondary outcomes: change in other HCC-related markers (des-gamma carboxyprothrombin, AFP-L3), blood tests for HCV RNA, SAMe metabolites, serum markers of oxidative stress, and quality of life.nnResults: A total of 110 patients were enrolled and 87 completed study. After the 24-week treatment, AFP declined among patients receiving SAMe (-1.9 ng/mL) and increased among patients receiving placebo (+5.9 ng/mL; p=0.16). Neither des-gamma carboxyprothrombin (DCP) nor AFP-L3 changed significantly with SAMe treatment. There were no significant differences in serum HCV RNA between groups. Blood levels of SAMe and S-adenosylhomocysteine (SAH) increased 3-5 fold among patients receiving SAMe and were unchanged in placebo group (p<0.01). Serum glutathione and methionine did not change significantly. Several components of quality of life improved among patients receiving SAMe. There were 5 serious adverse events in the placebo group and 7 in the SAMe group; none were attributable to SAMe.nnConclusions: SAMe administration for 24 weeks in patients with HCV-C and elevated AFP did not decrease AFP significantly nor alter liver function. SAMe significantly increased serum SAMe and SAH levels, but did not alter serum glutathione level or serum markers of oxidative stress.nnCitation Format: Timothy Morgan, Frank L. Meyskens, John Hoefs, Ke-Qin Hu, Tarek Hassanein, Thomas D. Boyer, Neville R. Pimstone, Kathy Osann, Rachel Gonzalez, L M. Rodriguez. SAMe versus placebo for the reduction of serum AFP in patients with hepatitis C cirrhosis and moderately elevated AFP: A randomized, placebo-controlled, double-blind phase II trial. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3247. doi:10.1158/1538-7445.AM2014-3247

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.

M1195 Phase II Chemoprevention Trial of Atorvastatin (ATOR), Sulindac (Sul), Oligofructose-Enriched Inulin (Ofei), or Ofei Placebo (Ofeip) Among Subjects at Increased Risk for Sporadic Colorectal Cancer (CRC): A Cancer Prevention Network (CPN) Trial

G A A b st ra ct s mortality and cancer related mortality. A secondary aim was to evaluate these effects across specific antioxidant compound, dose and duration of antioxidants supplementation. Using Cochrane Collaborationmethodology we searched for all randomized controlled trials (RCTs) from 1966 toMay 2009 (MEDLINE, Cochrane Controlled Clinical Trials Registry), comparing antioxidant supplements with placebo or no intervention on the occurrence of colorectal cancer or adenoma. The results expressed as relative risk (RR) and 95% confidence intervals (95% CI) were obtain using random and fixed effect meta-analysis. Twenty RCTs, including 268590 participants were eligible: 12 analyzing the colorectal cancer incidence included 250676 participants and 8 analyzing colorectal adenoma recurrence included 17914 participants. Antioxidant supplements had no significant effect on colorectal cancer incidence or colorectal adenoma recurrence (RR = 0, 94, 95% CI 0,84 1,06, p = 0,32) in a randomeffect meta-analysis. The antioxidant supplements had no significant effect on overall mortality (RR = 1,03, 95% CI 0,99 1,07, p = 0,12) or cancer related mortality (RR = 1,05, 95% CI 0,94 1,16, p = 0,38) in a random effect meta-analysis. Selenium supplementation was associated with a trend in reducing colorectal cancer incidence, (RR = 0,77, 95% CI 0,36 1,62, p = 0,49), colorectal adenoma recurrence (RR = 0,70, 95% CI 0,43 1,14, p = 0,16) and overall mortality (RR = 0,91, 95% CI 0,82-1,02, p = 0,09). Beta carotene alone was associated with a slight increase in colorectal cancer incidence (RR = 1,09, 95% CI = 0,92 1,29, p = 0,34) and in combinations with other antioxidants was associated with an increase in mortality (RR = 1,05, 95% CI = 0,99 1,11, p = 0,10). For both selenium and beta carotene, the effect was not statistically significant. Vitamin C and Vitamin E combination slightly reduced colorectal cancer incidence with no effect on overall mortality. This metaanalysis found no evidence in favor of a protective effect of the studied antioxidant supplements in the prevention of colorectal cancer or cancer related mortality. Only selenium supplementation might have anticarcinogenic effects and requires further research.