Faculty Bibliography

OBJECTIVE: The goal of this report is to describe the on going strategies, successes, challenges and solutions for recruitment in this multi-center, phase II chemoprevention trial targeting men at high risk for prostate cancer. METHODS: We developed and implemented a multi-center clinical trial in institutions with supportive infrastructure, lead by a recruitment team of experienced and committed physicians and clinical trial staff, implementing multi-media and community outreach strategies to meet recruitment goals. Screening logs were reviewed to identify trends as well as patient, protocol and infrastructure -related barriers impacting accrual and revisions to protocol implemented. RESULTS: Between January 2008 and February 2011 a total of 3547 individuals were prescreened with 94% (n=3092) determined to be ineligible based on diagnosis of cancer or benign biopsy results. Of these, 216 were considered eligible for further screening with 52% (n=113) declining to participate due to patient related factors and 14% (n=29) eliminated due to protocol-related criteria for exclusion. Ninety-four (94) subjects consented to participate with 34% of these subjects (n=74) meeting all eligibility criteria to be randomized to receive study agent or placebo. Across all sites, 99% of the recruitment of subjects in this clinical trial is via physician recruitment and referral with less than 1% responding to other recruitment strategies. CONCLUSION: A contemporary approach to subject recruitment and frequent evaluation is needed to assure responsiveness to emerging challenges to accrual and the evolving scientific literature. A focus on investing on improving systems for physician recruitment may be key to meeting recruitment target in chemoprevention trials.

In spite of the large number of nutrient-derived agents demonstrating promise as potential chemopreventive agents, most have failed to prove effectiveness in clinical trials. Critical requirements for moving nutrient-derived agents to recommendation for clinical use include adopting a systematic, molecular-mechanism based approach and utilizing the same ethical and rigorous methods such as are used to evaluate other pharmacological agents. Preliminary data on a mechanistic rationale for chemoprevention activity as observed from epidemiological, in vitro and preclinical studies, phase I data of safety in suitable cohorts, duration of intervention based on time to progression of preneoplastic disease to cancer and the use of a valid panel of biomarkers representing the hypothesized carcinogenesis pathway for measuring efficacy must inform the design of phase II clinical trials. The goal of this paper is to provide a model for evaluating a well characterized agent- Polyphenon E- in a phase II clinical trial of prostate cancer chemoprevention.

Melanin concentrating hormone (MCH) is a cyclic 19-amino-acid peptide expressed mainly in the hypothalamus. It is involved in the control of feeding behavior, energy homeostasis, and body weight. Administration of MCH-R1 antagonists has been proved to reduce food intake and cause weight loss in animal models. In the present study, a homology model of the human MCH-R1 was constructed using the crystal structure of bovine rhodopsin (PDB: 1u19) as a template. Based on the observation that MCH-R1 can bind ligands of high chemical diversity, the initial model was subjected to an extensive ligand-supported refinement using antagonists of different chemotypes. The refinement process involved stepwise energy minimizations and molecular dynamics simulations. The refined model was inserted into a pre-equilibrated DPPC/TIP3P membrane system and then simulated for 20 ns in complex with structurally diverse antagonists. This protocol was able to explain the SAR of MCH-R1 antagonists with diverse chemical structures. Moreover, it reveals new insights into the critical recognition sites within the receptor. This work represents the first detailed study of molecular dynamics of MCH-R1 inserted into a membrane-aqueous environment.