Polyphenon E For The Chemoprevention Of Colorectal Cancer
Frank A Sinicrope, Associate Professor
Mayo Clinic Coll Of Medicine, Rochester
Grant 1R01CA132991-01 from National Cancer Institute, IRG: ZRG1
Abstract: Green tea constituents including polyphenols have been convincingly shown to confer cancer preventive properties in animal model systems. Furthermore, epidemiologic studies have shown an association of green tea consumption and reduced risk of colorectal cancer. The major and most active green tea polyphenol is (-)-epigallocatechin-3-gallate (EGCG). Polyphenon E (PPE), a defined green tea polyphenol preparation containing about 65% EGCG and less than 0.1% caffeine, is currently being evaluated in the chemoprevention studies for human cancers. As outlined in Preliminary Results, dietary PPE reduced the total number of colorectal aberrant crypt foci (ACF) and decreased the percentage of ACF with high grade dysplasia in the azoxymethane (AOM) rodent model of colon carcinogenesis. These and other compelling preclinical data support the evaluation of PPE for colon cancer prevention. We propose to conduct a randomized phase II chemoprevention trial of PPE versus placebo to regress rectal ACF among subjects at high risk for recurrent colorectal neoplasia. The primary study endpoint will be the percent change in ACF number in the rectum at 6 months of continuous PPE treatment compared to baseline using magnifying chromoendoscopy. ACF characteristics (size, morphology, histopathology) will also be studied. Drug levels and tissue biomarkers selected based upon mechanistic insights from a rodent carcinogenesis model will be evaluated in ACF and normal mucosa. Preclinical and human studies support the utility of ACF, putative precursors of human adenomatous polyps, as a surrogate endpoint biomarker (SEB) for chemoprevention trials. In carcinogen-induced colon cancer in rodents, ACF serve as an SEB for adenomas and carcinomas. In observational studies, significant correlations were found between the number of ACF, the presence and size of dysplastic foci, and the number of adenomas or prior colorectal cancer. Importantly, short-term administration of the nonselective COX inhibitor sulindac was shown to regress rectal ACF in high risk patients in a small, open-label trial from Japan. ACF consist of enlarged and thickened crypts that can be detected in human colorectal mucosa using magnifying chromoendoscopy. In the proposed study, we examine the chemopreventive efficacy of PPE and specifically test the hypothesis that PPE can prevent/regress rectal ACF in subjects at increased CRC risk. Green tea polyphenols are effective chemopreventive agents in animal models of colon cancer. We will determine the effect of polyphenon E on precursor lesions of colorectal adenomas in patients at high risk of colorectal cancer
Project start date: 2008-08-01
Project end date: 2013-05-31
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Grants awarded to Frank A Sinicrope
Clinical Significance Of Apoptosis In Colon Cancer
Frank A Sinicrope, Associate Professor
Mayo Clinic Coll Of Medicine, Rochester 200 1st St Sw Rochester, Mn 55905
Grant 5R01CA104683-04 from National Cancer Institute, IRG: CONC
Abstract: Tumor stage remains the most important prognostic variable in human colorectal cancers and is used to determine the need for adjuvant chemotherapy. However, there is considerable stage-independent variability in clinical outcome. Despite adjuvant treatment, 30-40% of stage III patients will recur and die of their disease. Accordingly, additional prognostic markers are needed to better define the subset of patients who would benefit most from adjuvant chemotherapy. Prognostic and predictive markers would also enable a more selective, tailored and molecularly- targeted treatment approach. We propose to study apoptotic regulatory proteins in >1,000 well characterized stage II and III colon cancers from patients treated in 5-fluorouracil-based adjuvant therapy trials conducted by the North Central Cancer Treatment Group (NCCTG) and the National Cancer Institute of Canada. Some of these trials include untreated control arms enabling us to determine predictive utility. Defects in the regulation of apoptosis have been shown to contribute to tumor progression and metastasis, and can confer resistance to anti-cancer therapies. Two distinct apoptotic signalling pathways have been defined and include the membrane death receptor (DR) pathway and the mitochondrial pathway. Engagement of the mitochondrial pathway results in cytochrome release which can be attenuated by anti-apoptotic Bcl-2 and by inhibitors of apoptosis proteins (lAPs), which bind to and inhibit caspases. The DR pathway is engaged by members of the TNF superfamily which act as natural ligands for specific DRs. DRs mediate apoptosis through their cytoplasmic death domains. Decoy receptors lack death domains but can compete for ligand binding. Both apoptotic pathways involve activation of intracellular cysteine proteases known as caspases that become activated through proteolytic processing and lead to apoptosis. Our preliminary data indicate that apoptotic regulatory proteins display tumor-specific overexpression in human colon cancers. Moreover, our data suggest that negative and positive regulators of the mitochondrial pathway are significantly associated with shorter and longer patient survival rates, respectively. Recent data also suggest that DR4 is overexpressed in colon cancers and can confer prognostic information, as can decoy receptor 3, an inhibitor of Fas signalling. We propose to determine the predictive and prognostic significance of apoptotic regulatory proteins in 1,324 colon cancer patients. Tissue microarrays will be created from paraffin blocks to enable the efficient immunohistochemical analysis of multiple apoptosis-regulating proteins Our study results will then be correlated with previously determined markers including microsatellite instability, allelic loss, and DNA ploidy and multivariate models will be created to determine the most significant markers for incorporation into a prospective adjuvant therapy trial involving 3,750 patients to be conducted by the NCCTG/Intergroup mechanism.
Keywords: apoptosis, biomarker, colorectal neoplasm, neoplasm /cancer classification /staging, prognosis, BCL2 gene /protein, cysteine endopeptidase, fluorouracil, genetic manipulation, neoplasm /cancer genetics, protease inhibitor, clinical research, human tissue, immunocytochemistry, microarray technology, receptor binding
Project start date: 2003-09-30
Project end date: 2008-08-31
5R01CA104683-04 (2006): $253773
5R01CA104683-03 (2005): $259880
5R01CA104683-02 (2004): $259880
1R01CA104683-01 (2003): $259880
A THREE ARM PHASE II CHEMOPREVENTION TRIAL IN ADENOMATOU
Frank A Sinicrope, Associate Professor
Gas Med Oncology & Digest Disuniversity Of Texas Md Anderson Can Ctr
cancer Center
houston, Tx 770304009
Grant 5N01CN095040-001 from Division Of Cancer Prevention And Control, IRG:
Abstract: Persons with familial adenomatous polyposis (FAP) have a nearly 100 percent lifetime risk of cancer, most often involving the upper or lower GI tract. Development of a cancer chemopreventive agent that could reduce this risk would offer a significant benefit. Nonsteroidal anti-inflammatory agents (NSAIDs) have shown efficacy in this disease by regressing prevalent colorectal adenomas. This trial seeks to determine the relative efficacy and tolerability of a promising agent combination (NSAID + difluoromethylornithine), versus an NSAID alone, versus placebo given over 6 months in 50 persons with FAP. The primary endpoint will evaluate the quantitative reduction in several parameters of colorectal adenomas following a six month period of administration. Other objectives include the evaluation of the treatments´ efficacy against duodenal adenomas, and a panel of efficacy- and drug effect-biomarkers in duodenal and colorectal mucosa. Biomarker assessments are anticipated to improve mechanistic insights and iterative agent identification/development for this disease
Keywords: adenomatous polyp, chemoprevention, combination antineoplastic therapy, difluoromethylornithine, human therapy evaluation, nonsteroidal antiinflammatory agent biomarker, cancer prevention, clinical trial, colorectal neoplasm clinical research, human subject, placebo
Project start date: 1999-09-30
Project end date: 2001-09-29
5N01CN095040-001 (2000): $500000
1N01CN095040-000 (1999): $793013
Polyphenon E For The Chemoprevention Of Colorectal Cancer
Frank A Sinicrope, Associate Professor
Mayo Clinic Coll Of Medicine, Rochester
Grant 1R01CA132991-01 from National Cancer Institute, IRG: ZRG1
Abstract: Green tea constituents including polyphenols have been convincingly shown to confer cancer preventive properties in animal model systems. Furthermore, epidemiologic studies have shown an association of green tea consumption and reduced risk of colorectal cancer. The major and most active green tea polyphenol is (-)-epigallocatechin-3-gallate (EGCG). Polyphenon E (PPE), a defined green tea polyphenol preparation containing about 65% EGCG and less than 0.1% caffeine, is currently being evaluated in the chemoprevention studies for human cancers. As outlined in Preliminary Results, dietary PPE reduced the total number of colorectal aberrant crypt foci (ACF) and decreased the percentage of ACF with high grade dysplasia in the azoxymethane (AOM) rodent model of colon carcinogenesis. These and other compelling preclinical data support the evaluation of PPE for colon cancer prevention. We propose to conduct a randomized phase II chemoprevention trial of PPE versus placebo to regress rectal ACF among subjects at high risk for recurrent colorectal neoplasia. The primary study endpoint will be the percent change in ACF number in the rectum at 6 months of continuous PPE treatment compared to baseline using magnifying chromoendoscopy. ACF characteristics (size, morphology, histopathology) will also be studied. Drug levels and tissue biomarkers selected based upon mechanistic insights from a rodent carcinogenesis model will be evaluated in ACF and normal mucosa. Preclinical and human studies support the utility of ACF, putative precursors of human adenomatous polyps, as a surrogate endpoint biomarker (SEB) for chemoprevention trials. In carcinogen-induced colon cancer in rodents, ACF serve as an SEB for adenomas and carcinomas. In observational studies, significant correlations were found between the number of ACF, the presence and size of dysplastic foci, and the number of adenomas or prior colorectal cancer. Importantly, short-term administration of the nonselective COX inhibitor sulindac was shown to regress rectal ACF in high risk patients in a small, open-label trial from Japan. ACF consist of enlarged and thickened crypts that can be detected in human colorectal mucosa using magnifying chromoendoscopy. In the proposed study, we examine the chemopreventive efficacy of PPE and specifically test the hypothesis that PPE can prevent/regress rectal ACF in subjects at increased CRC risk. Green tea polyphenols are effective chemopreventive agents in animal models of colon cancer. We will determine the effect of polyphenon E on precursor lesions of colorectal adenomas in patients at high risk of colorectal cancer
Project start date: 2008-08-01
Project end date: 2013-05-31
Aberrant Crypt Foci As A Biomarker For Chemoprevention
Frank A Sinicrope, Associate Professor
Mayo Clinic Coll Of Medicine, Rochester 200 1st St Sw Rochester, Mn 55905
Grant 5R01CA113681-02 from National Cancer Institute, IRG: ZRG1
Abstract: Chemoprevention trials have utilized adenoma recurrence as the primary endpoint based upon multiple lines of evidence establishing adenomas as precursor lesions of colorectal cancers. These trials require large study populations followed for extended time periods and utilize extensive resources. Accordingly, there is a critical need to identify a surrogate endpoint biomarker (SEB) that can predict treatment efficacy and whose validation would enable smaller, shorter-term and less costly prevention trials. A promising candidate SEB is the aberrant crypt foci (ACF). ACF are putative precursors of adenomas and carcinomas based upon their age-related prevalence, left-sided predominance, frequency of dysplasia, and association with prior/current neoplasia. ACF can be detected and quantified in the human colorectum using magnification chromoendoscopy. Studies in animal models of colon cancer indicate that ACF can serve as a SEB for chemopreventive efficacy and the NSAID sulindac was shown to regress ACF in Japanese subjects. To date, limited data are available on ACF in the U.S. population and an important aim of this proposal is to identify, quantify, and characterize ACF in a high risk population. To this end, we propose a randomized, placebo controlled trial in patients with prior advanced colonic adenomas or carcinomas evaluating aspirin alone and in combination with calcium carbonate or difluoromethylornithine over a 12 month period. Agent selection is based upon compelling preclinical and human data. The primary study endpoint will be the percent change in ACF number in the left colon at 12 month compared to baseline using magnifying chromoendoscopy. ACF characteristics (size/morphology, histopathology) will be determined and tissue biomarkers will be evaluated in ACF or normal mucosa. These will include drug targets, i.e., prostaglandin E2 and mucosal polyamine levels, apoptotic and proliferative indices, downstream effectors of EGFR, i.e., cyclooxygenase-2 (COX-2) and cyclin D1, and COX-2-dependent apoptotic regulatory genes based upon preliminary data. Gene expression profiling of ACF will also be performed. In an effort to determine the natural history of ACF, adenoma recurrence will be determined at the 12 month colonoscopy and patients will be followed prospectively to record surveillance colonoscopy data over a 36 month period post study entry.
Project start date: 2006-09-01
Project end date: 2009-07-31
5R01CA113681-02 (2007): $462908
1R01CA113681-01A1 (2006): $503681
CALCIUM AND ASPIRIN PREVENTION TRIAL
Frank A Sinicrope, Associate Professor
University Of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009
Grant 5R01CA064132-03 from National Cancer Institute, IRG: ZRG3
Abstract: Adapted from the investigator s ) Modification of the carcinogenic process by dietary supplements and pharmacologic agents is a major emphasis in colon cancer prevention research. Two sequential studies are proposed to investigate the role of combined calcium and aspirin supplementation in colon cancer chemoprevention. The two agents are chosen because (a) extensive epidemiologic and laboratory data support their chemopreventive potential, (b) their safety profile has been well delineated in other health conditions in which they are of benefit, (c) they may have complementary mechanisms of action, and (d) the research team has considerable experience with these agents. Target populations will be subjects with a prior history of sporadic adenomatous polyps of the colon within 5 years of entry and no history of previous malignancy. A preliminary Phase 2a trial is designed to determine the minimum dose of aspirin which has relevant biologic activity. A subsequent randomized, double-blind, placebo controlled Phase 2b trial is designed to test the single and combined chemopreventive effects of aspirin and calcium, given for 12 weeks. The aspirin dose will be determined in the phase 2a trial, and the calcium dose will be the previously demonstrated effective dose of 2000 mg/d. The primary endpoints will be colonic mucosal prostaglandin E2 levels and epithelial proliferation indices measured by PCNA methodology. The investigators hypothesize that calcium and aspirin will have a synergistic, risk reducing effect on the colonic mucosa in subjects with a history of adenomatous polyps. The study will be performed in a network of gastroenterologists with access to a large population of adenomatous polyp patients and extensive experience in chemoprevention trials. Data from the phase 2b study will serve to construct a phase 3 study on recurrent polyps.
Keywords: aspirin, calcium, chemoprevention, colon neoplasm, dietary supplement, adenomatous polyp, biomarker, cell cycle, clinical trial, combination therapy, dosage, drug screening /evaluation, gastrointestinal epithelium, intestinal mucosa, proliferating cell nuclear antigen, prostaglandin E, biopsy, human subject, nutrition related tag, placebo
Project start date: 1995-09-21
Project end date: 2001-08-31
5R01CA064132-03 (1997): $293806
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