Sherri Patterson

THE EFFECT OF CELECOXIB, A CYCLOOXYGENASE-2 INHIBITOR, IN FAMILIAL ADENOMATOUS POLYPOSIS

BACKGROUND Patients with familial adenomatous polyposis have a nearly 100 percent risk of colorectal cancer. In this disease, the chemopreventive effects of nonsteroidal antiinflammatory drugs may be related to their inhibition of cyclooxygenase-2. METHODS We studied the effect of celecoxib, a selective cyclooxygenase-2 inhibitor, on colorectal polyps in patients with familial adenomatous polyposis. In a double-blind, placebo-controlled study, we randomly assigned 77 patients to treatment with celecoxib (100 or 400 mg twice daily) or placebo for six months. Patients underwent endoscopy at the beginning and end of the study. We determined the number and size of polyps from photographs and videotapes; the response to treatment was expressed as the mean percent change from base line. RESULTS At base line, the mean (+/-SD) number of polyps in focal areas where polyps were counted was 15.5+/-13.4 in the 15 patients assigned to placebo, 11.5+/-8.5 in the 32 patients assigned to 100 mg of celecoxib twice a day, and 12.3+/-8.2 in the 30 patients assigned to 400 mg of celecoxib twice a day (P=0.66 for the comparison among groups). After six months, the patients receiving 400 mg of celecoxib twice a day had a 28.0 percent reduction in the mean number of colorectal polyps (P=0.003 for the comparison with placebo) and a 30.7 percent reduction in the polyp burden (the sum of polyp diameters) (P=0.001), as compared with reductions of 4.5 and 4.9 percent, respectively, in the placebo group. The improvement in the extent of colorectal polyposis in the group receiving 400 mg twice a day was confirmed by a panel of endoscopists who reviewed the videotapes. The reductions in the group receiving 100 mg of celecoxib twice a day were 11.9 percent (P=0.33 for the comparison with placebo) and 14.6 percent (P=0.09), respectively. The incidence of adverse events was similar among the groups. CONCLUSIONS In patients with familial adenomatous polyposis, six months of twice-daily treatment with 400 mg of celecoxib, a cyclooxygenase-2 inhibitor, leads to a significant reduction in the number of colorectal polyps.

The Safety and Efficacy of Celecoxib in Children With Familial Adenomatous Polyposis

OBJECTIVES:Celecoxib is approved as an adjunctive chemopreventive agent in adults with familial adenomatous polyposis (FAP). Its safety and efficacy for colorectal polyps in children is unknown. We evaluated the short-term (3 months) safety and preliminary efficacy of celecoxib in children with FAP.METHODS:This was a phase I, dose-escalation trial, with three successive cohorts of six children. Children of ages 10–14 years with APC gene mutations and/or adenomas with a family history of FAP were studied at M.D. Anderson Cancer Center and the Cleveland Clinic. Colonoscopy was performed at baseline and month 3. Random assignment was in a 2:1 generic:placebo ratio, escalating from cohort 1 (4 mg/kg/day) to cohort 2 (8 mg/kg/day) to cohort 3 (16 mg/kg/day). Adherence and adverse event (AE) monitoring was conducted at 2-week intervals during drug administration. Safety profile, difference in number, and percent change in colorectal polyps were compared among the four treatments (placebo and the three dose-escalation groups).RESULTS:Eighteen subjects completed drug dosing and both colonoscopies. Median age was 12.3 years (56% female). No clinically meaningful differences in AEs were seen between placebo subjects and subjects at any of the three celecoxib doses. Median polyp count at baseline was 31. There was a 39.1% increase in the number of polyps in placebo subjects at month 3, whereas in the highest dose celecoxib group, 16 mg/kg/day, a 44.2% reduction was seen (P=0.01).CONCLUSIONS:Celecoxib at a dose of 16 mg/kg/day, corresponding to the adult dose of 400 mg BID, is safe, well tolerated, and significantly reduced the number of colorectal polyps in children with FAP.

Chemoprevention – History and general principles

Our current understanding of tumourigenesis suggests that cancer develops as a series of cumulative genetic and epigenetic derangements across time culminating in a clone of cells differing from its population of origin in terms of cellular identity, growth control, and its contextual relationship to its environment. Our increasing knowledge of the timing, sequence, frequency, and specific implications of these changes provides unique opportunities for earlier identification of aberrations and preventive interventions. Here we discuss the fundamentals of cancer prevention including the targets, cohorts, agents, endpoints, mechanistic biomarkers, designs, and strategies employed in preventive drug development. There have been many notable successes in this field such as the identification and development of tamoxifen and raloxifene for breast cancer risk reduction, instillational BCG and valrubicin for treatment of preinvasive bladder cancer, and a variety of topical and systemic agents that effectively treat preinvasive neoplastic lesions of the skin. A variety of null or negative developmental endeavours have occurred as well, including trials of beta-carotene for lung cancer prevention, nutritional modifications for colorectal adenoma prevention, and most recently, selenium and alpha-tocopherol for prostate cancer prevention. A third category of prevention trials can be summarized as investigationally successful, but not achieving regulatory success. The development of finasteride and dutasteride for prostate cancer prevention, and celecoxib for colorectal neoplasia prevention fall into this category. In less than four decades, cancer chemoprevention has transformed from a concept to an achievable reality.

An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis

Background and aim Although Non-steroidal anti-inflammatory drugs reduce colorectal adenoma burden in familial adenomatous polyposis (FAP), the utility of combining chemopreventive agents in FAP is not known. We conducted a randomised trial of celecoxib (CXB) versus CXB+diflouromethylornithine (DFMO) to determine the synergistic effect, if any. Methods The primary endpoint was % change in adenoma count in a defined field. Secondary endpoints were adenoma burden (weighted by adenoma diameter) and video review of entire colon/rectal segments. Adverse event (AEs) were monitored by National Cancer Institution toxicity criteria. Results 112 subjects were randomised: 60 men and 52 women at a mean age of 38 years. For the 89 patients who had landmark-matched polyp counts available at baseline and 6 months, the mean % change in adenoma count over the 6 months of trial was −13.0% for CXB+DFMO and −1.0% for CXB (p=0.69). Mean % change in adenoma burden was −40% (CXB+DFMO) vs −27% (CXB) (p=0.13). Video-based global polyp change was −0.80 for CXB+DFMO vs −0.33 for CXB (p=0.03). Fatigue was the only significant AE, worse on the CXB arm (p=0.02). Conclusions CXB combined with DFMO yielded moderate synergy according to a video-based global assessment. No significant difference in adenoma count, the primary endpoint, was seen between the two study arms. No evidence of DFMO-related ototoxicity was seen. There were no adverse cardiovascular outcomes in either trial arm and no significant increase in AEs in the CXB+DFMO arm of the trial. Differences in outcomes between primary and secondary endpoints may relate to sensitivity of the endpoint measures themselves. Trial registration number ClinicalTrials.gov number N01-CN95040.

Celecoxib treatment alters the gene expression profile of normal colonic mucosa.

A clinical trial was recently conducted to evaluate the safety and efficacy of a selective inhibitor of cyclooxygenase-2 (celecoxib) in hereditary nonpolyposis colon cancer patients. In a randomized, placebo-controlled phase I/II multicenter trial, hereditary nonpolyposis colon cancer patients and gene carriers received either celecoxib at one of two doses or placebo. The goal was to evaluate the effects of these treatment arms on a number of endoscopic and tissue-based biomarker end points after 12 months of treatment. As part of this trial, we analyzed gene expression by cDNA array technology in normal descending (rectal) colonic mucosa of patients before and after treatment with celecoxib or placebo. We found that treatment of patients with celecoxib at recommended clinical doses (200 and 400 mg p.o. bid), in contrast to treatment with placebo, leads to changes in expression of >1,400 genes in the healthy colon, although in general, the magnitude of changes is <2-fold. Twenty-three of 25 pairs of colon biopsies taken before and after celecoxib treatment can be classified correctly by the pattern of gene expression in a leave-one-out cross-validation. Immune response, particularly T- and B-lymphocyte activation and early steps of inflammatory reaction, cell signaling and cell adhesion, response to stress, transforming growth factor-β signaling, and regulation of apoptosis, are the main biological processes targeted by celecoxib as shown by overrepresentation analysis of the distribution of celecoxib-affected genes across Gene Ontology categories. Analysis of possible cumulative effects of celecoxib-induced changes in gene expression indicates that in healthy colon, celecoxib may suppress the immune response and early steps of inflammation, inhibit formation of focal contacts, and stimulate transforming growth factor-β signaling. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1382–91)

Conference report: Seventh annual AACR international conference on frontiers in cancer prevention research

In November, 2008 the AACR held the Seventh Annual Frontiers in Cancer Prevention Research meeting in Washington, DC. At this meeting, a wide range of cutting-edge cancer prevention research was presented. This summary highlights some of the most impactful presentations with a focus on the interaction between inflammation, infections, the immune system, and tumor microenvironment in promoting cancer. Several of these presentations described targeting host-tumor interactions as a means for cancer prevention. As discussed below, this meeting continues to represent all phases of cancer prevention research including epidemiologic studies, behavioral and lifestyle interventions, carcinogenesis research, preclinical studies testing novel preventive interventions, and the results of early- and late-phase cancer prevention trials. Major advances presented at the 2008 meeting included studies showing that immune cells can be either protumorigenic or antitumorigenic, efforts to develop more comprehensive human papillomavirus vaccines to more effectively prevent cervical cancer and other human papillomavirus–related cancers, controversial studies of vitamin D and cancer risk, and studies of single-nucleotide polymorphisms to better assess cancer risk. These and the other presentations at this meeting continue to provide strong support for the concept that cancer will be most effectively controlled by applying modern cancer prevention strategies

Convergence of nanotechnology and cancer prevention: Are we there yet?

Nanotechnology is emerging as a promising modality for cancer treatment; however, in the realm of cancer prevention, its full utility has yet to be determined. Here, we discuss the potential of integrating nanotechnology in cancer prevention to augment early diagnosis, precision targeting, and controlled release of chemopreventive agents, reduced toxicity, risk/response assessment, and personalized point-of-care monitoring. Cancer is a multistep, progressive disease; the functional and acquired characteristics of the early precancer phenotype are intrinsically different from those of a more advanced anaplastic or invasive malignancy. Therefore, applying nanotechnology to precancers is likely to be far more challenging than applying it to established disease. Frank cancers are more readily identifiable through imaging and biomarker and histopathologic assessment than their precancerous precursors. In addition, prevention subjects routinely have more rigorous intervention criteria than therapy subjects. Any nanopreventive agent developed to prevent sporadic cancers found in the general population must exhibit a very low risk of serious side effects. In contrast, a greater risk of side effects might be more acceptable in subjects at high risk for cancer. Using nanotechnology to prevent cancer is an aspirational goal, but clearly identifying the intermediate objectives and potential barriers is an essential first step in this exciting journey. Cancer Prev Res; 7(10); 973–92. ©2014 AACR.

Modelling a dream: the molecular prevention of pancreatic cancer

Pancreatic cancer is a frequent and devastating cause of morbidity and mortality in many parts of the world with a 5 year survival of only 5%.1 Unfortunately, these dismal statistics have not improved appreciably over the last 30 years despite an explosive growth in our understanding of the diseases pathogenesis. Indeed, a recent model of human pancreatic cancer provides important histological and molecular insights,2 but for the most part, these insights await translation into improved markers for risk assessment, new agents for prevention and therapy, as well as intermediate endpoints that could prove useful in guiding intervention trials. Despite these translational limitations, our growing knowledge of human cancer development has stimulated the development of many new, genetically driven rodent models that promise to provide novel mechanistic insights into cancer development and progression, and/or serve as improved preclinical systems in which to evaluate promising preventive or therapeutic agents. Of course, the relevance of these models to human applications depends on several factors.3 4 Fundamentally, the most promising new animal models should: (1) employ genetic manipulations that mimic key molecular determinants of human disease—optimally, in nature, magnitude, timing, and frequency; (2) reflect histopathological and phenotypic features of human disease that evolve over time; and (3) offer reproducible results across time and various laboratories. Additional desirable features of somewhat lesser importance include: (1) ready public access, (2) efficiency of use (eg, regarding the frequency and timing of meaningful endpoints), (3) modest cost, (4) breeding efficiencies (eg, for generation and maintenance of the colony), and (5) an intact immune system. When an animal model is used to …

Aspirin: anticolorectal adenocarcinoma activity in the adjuvant arena?

Evaluation of: Chan AT, Ogino S, Fuchs CS: Aspirin use and survival after diagnosis of colorectal cancer. JAMA 302, 649-659 (2009). Colorectal cancer (CRC) is the second most common cause of cancer-related deaths in Americans. In prior observational studies, aspirin has been associated with significant reductions in colorectal adenoma recurrence, CRC incidence, CRC-associated mortality and overall mortality. In this study of data from two large, long-term cohort studies, Chan et al. identify significant inverse associations in both CRC-related mortality and overall mortality among patients with stage I-III CRC using aspirin versus nonusers. The absolute risk reductions in both parameters in aspirin users are in the order of 4%, but aspirins potential benefits are restricted to patients with COX-2-overexpressing tumors. The feasibility and impact of aspirin as an adjuvant therapy for nonmetastatic CRC needs confirmation in randomized trials to answer remaining questions regarding the most appropriate dose, frequency and duration of administration, as well as to estimate the relative benefits versus risks of treatment in this setting.

Abstract C40: Organochlorine and organophosphate pesticide exposure in children and adolescents of Mexican origin residing in the Lower Rio Grande Valley of Texas

Background: Children and adolescents of Mexican origin residing in the Lower Rio Grande Valley (LRGV) of Texas, USA were evaluated for risk of exposure to organochlorine (OC) and organophosphate (OP) pesticides. This pilot study summarizes the lipid adjusted serum concentrations of OCs and the creatinine corrected urine concentrations of OPs obtained from study participants. Methods: The lipid adjusted serum concentrations of OCs (in ppb on a lipid-weight basis) along with creatinine corrected urine concentrations of OPs (in µg/g of creatinine) were measured and compared to the US national data reported by the National Health and Nutrition Examination Survey (NHANES). Descriptive statistics, including geometric means (GMs) and 95% confidence intervals (CIs), were used to summarize the distribution of concentration levels. Scatter plots were generated to visually assess distributions and to identify outlying values relative to the positioning of the NHANES 95th percentile. Half of the limit of detection (LOD) was substituted for cases where concentration levels were below LOD. Results: Sixty children and adolescents participated in the study, with 58 providing serum and urine samples for OC and OP analyses. Of the 9 OC pesticides analyzed, p,p9-DDE had the largest variability and highest frequency of lipid adjusted serum concentrations above the LOD. The GM for p,p9-DDE was 107.1 (ppb), similar to the GM of 105 (ppb) for p,p9-DDE reported by the NHANES. However, our inspection of the distribution of p,p9-DDE concentrations identified two participants with levels above 1,000 (ppb). Outlying values of 127 and 48.5 (ppb) were also identified for p,p9-DDT and gamma-HCCH, respectively. Of the 6 OP pesticides analyzed and specifically for participants 5 to 11 years of age, creatinine corrected urine concentrations of DMP had the largest variability and contained an outlying value of 64.8 (µg/g). For participants 12 to 18 years of age, the creatinine corrected urine concentrations of all 6 OPs were at or below the 95th percentile reported by the NHANES for adolescents 12 to 19 years of age. Conclusion: Although the OCs and OPs analyzed in this study were indicative of concentration levels within the distributional range of the US national data reported by the NHANES, the p,p9-DDE concentration levels of two children exceeded the 95th percentile for the US population by more than two-fold. This warrants further investigation given that p,p9-DDE is a known derivative of DDT which has been banned in the US for more than 40 years. Citation Format: Mike Hernandez, Celia Garcia-Prieto, Maria Hernandez-Valero, Sherri L. Patterson, Yisheng Li, Richard A. Hajek, Lovell A. Jones, Ernest Hawk. Organochlorine and organophosphate pesticide exposure in children and adolescents of Mexican origin residing in the Lower Rio Grande Valley of Texas. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C40.