Alberts, David S.

Abstract Background Although a number of cancer chemopreventive agents have now been evaluated in phase II and phase III clinical trials that assess their efficacy and tolerability in both high risk and general populations, few have shown clear efficacy and uptake of approved agents has been disappointingly low. Therefore, chemopreventive agents should undergo rigorous screening prior to clinical trial evaluation in order to improve the selection of suitable agents for testing in large, expensive multi-center phase III trials. The aim of this study is to develop a descriptive method for prioritizing candidate agents for further development. Methods This framework was developed through a systematic literature review of Pubmed/Medline, Embase and The Cochrane Library. A semi-quantitative assessment focusing on efficacy and toxicity/tolerability was established based on expert input. Data from clinical trials, cancer epidemiological, observational and preclinical studies, including in vivo and in vitro basic research, was used to retrospectively evaluate the clinical application and effectiveness of cancer chemopreventive agents. Two chemopreventive agents with either a positive (aromatase inhibitors (AIs) for breast cancer) or negative (selenium for lung cancer) phase III clinical trial outcome were subsequently evaluated to determine the usefulness of the framework. Results Chemopreventive agents must reduce or reverse the process of carcinogenesis in normal or pre-malignant tissue with minimal toxicity. Evaluation of efficacy included data from preclinical and animal models, epidemiological studies, and clinical trials (both early phase trials in the organ of interest as well as secondary endpoints from other relevant studies). Agent suitability evaluation included assessment of toxicities, tolerability, and agent specific attributes (PK/PD, bioavailability, dosing, etc.). Examination of selenium and AI historical data in these categories revealed strong concordance with phase III outcomes. The detailed descriptive evaluation of the agents will be presented. Conclusion This framework provides a descriptive paradigm for cancer chemopreventive agent evaluation through systematic and rigorous interrogation. Thorough, standardized evaluation of all available preclinical, epidemiological, and clinical data should be strongly encouraged to better inform the investments required for clinical trials. Citation Format: Naomi Walsh, David S. Alberts, Powel Brown, Paul Limburg, Mark Sherman, Eva Szabo. Framework for clinical evaluation of chemopreventive agents: Defining criteria for future assessment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4662. doi:10.1158/1538-7445.AM2015-4662

Abstract COX inhibitors reduce colorectal adenoma recurrence by up to 45% and selenium supplementation may prevent colorectal cancer. Following colonoscopic adenoma resection, 1,600 men and women, ages 40 to 80 years, were randomized to celecoxib (400 mg daily), a selective COX-2 inhibitor, and/or selenium (200 μg daily as selenized yeast), or double placebo. The trial was initiated in November 2001. The primary trial endpoint is adenoma recurrence in each intervention group compared with placebo, as determined by surveillance colonoscopy conducted three to five years after baseline. Randomization was stratified by use of low-dose aspirin (81 mg) and clinic site. Following reports of cardiovascular toxicity associated with COX-2 inhibitors, the celecoxib arm was discontinued in December 2004 when 824 participants had been randomized. Accrual continued with randomization to selenium alone or placebo. Randomization of the originally planned cohort (n = 1,621) was completed in November 2008. A further 200 patients with one or more advanced adenomas (denoting increased risk for colorectal cancer) were accrued to enhance statistical power for determining intervention efficacy in this higher-risk subgroup. Accrual of the total cohort (n = 1,824) was completed in January 2011. Baseline cohort characteristics include: mean age 62.9 years; 65% male; body mass index (BMI) 29.1 ± 5.1; 47% taking low-dose aspirin while on trial; 20% with three or more adenomas; and 38% with advanced adenomas. Intervention effects on adenoma recurrence will be determined, and their modification by genetic background and baseline selenium level. The effect of selenium supplementation on risk for type II diabetes will also be reported. Cancer Prev Res; 5(12); 1381–93. ©2012 AACR.

Abstract Cutaneous squamous cell carcinoma (SCC) occurs commonly and can metastasize. Identification of specific molecular aberrations and mechanisms underlying the development and progression of cutaneous SCC may lead to better prognostic and therapeutic approaches and more effective chemoprevention strategies. To identify genetic changes associated with early stages of cutaneous SCC development, we analyzed a series of 40 archived skin tissues ranging from normal skin to invasive SCC. Using high-resolution array-based comparative genomic hybridization, we identified deletions of a region on chromosome 10q harboring the INPP5A gene in 24% of examined SCC tumors. Subsequent validation by immunohistochemistry on an independent sample set of 71 SCC tissues showed reduced INPP5A protein levels in 72% of primary SCC tumors. Decrease in INPP5A protein levels seems to be an early event in SCC development, as it also is observed in 9 of 26 (35%) examined actinic keratoses, the earliest stage in SCC development. Importantly, further reduction of INPP5A levels is seen in a subset of SCC patients as the tumor progresses from primary to metastatic stage. The observed frequency and pattern of loss indicate that INPP5A, a negative regulator of inositol signaling, may play a role in development and progression of cutaneous SCC tumors. Cancer Prev Res; 3(10); 1277–83. ©2010 AACR.