Epidemiological and laboratory studies have identified epigallocatechin gallate (EGCG) in green tea polyphenols (GTP), as the most potent chemopreventive agent that can induce apoptosis, suppress the formation and growth of human cancers including prostate cancer (CaP). Our group has shown that EGCG and Polyphenon E, potently and selectively inhibits the proteasomal chymotrypsin-like activities in intact human CaP cells and consequently accumulates IkB-o and p27 proteins, leading to growth arrest. The pharmacokinetics and safety of several preparations of GTP, specifically Polyphenon E at doses ranging from 600-1200 mgs EGCG have been demonstrated in phase I trials. In a preliminary study, Bettuzzi et al26, demonstrated the safety and efficacy of GTPs (400 mgs of EGCG/day) for chemoprevention of CaP in 60 men diagnosed with HGPIN, with only 1 tumor diagnosed among the GTP-treated men (3%), compared to 9 cancers in the placebo-treated arm (30%). Based on the promising results of our studies and that of others, including Bettuzzi et al's results, a definitive phase II clinical trial, powered to examine the effects of EGCG in inhibiting the progression to CaP in larger cohort diagnosed with HGPIN lesions, is a logical next step. The central hypothesis for the proposed phase II clinical trial is that men with HGPIN who receive Polyphenon E at a dose of 400 mg EGCG/day for 12 months will significantly decrease progression to CaP compared with men with HGPIN who take placebo. We hypothesize that the primary pathway by which tea catechins, specifically EGCG will induce prostate epithelial cell apoptosis, is via the proteasome inhibition pathway, resulting in inhibition of prostate cell survival and induction of apoptosis, thereby decreasing progression from HGPIN to prostate cancer. To test this hypothesis, our specific aims will be to recruit, randomize and treat 240 (120 men/arm) men diagnosed with HGPIN to receive Polyphenon E containing 400 mg of EGCG or placebo for one year and evaluate compliance, symptoms, toxicity, evaluate HGPIN and prostate cancer incidence at 6 and 12 months and treatment-related inhibition of proteasome activity and induction of apoptosis in prostate tissue biopsies. Our other aim is to explore other potential mechanisms to develop and refine models of fundamental molecular pathways for EGCG and GTP. Our proposal is innovative, timely, and provides a robust approach to evaluate a promising nutrient-based chemopreventive agent against a disease of major public health significance. If the safety and the effects of Polyphenon E for chemoprevention of CaP are demonstrated, we plan to then examine the long-term effects of this agent in a large Phase III trial.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1-RPRB-5 (J1))
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Parnes, Howard L
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H. Lee Moffitt Cancer Center & Research Institute
United States
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Kumar, Nagi B; Pow-Sang, Julio; Egan, Kathleen M et al. (2015) Randomized, Placebo-Controlled Trial of Green Tea Catechins for Prostate Cancer Prevention. Cancer Prev Res (Phila) 8:879-87
Kumar, Nagi B; Dhurandhar, Medha; Aggarwal, Bharat et al. (2013) Proceedings of the Indo-U.S. bilateral workshop on accelerating botanicals/biologics agent development research for cancer chemoprevention, treatment, and survival. Cancer Med 2:108-15
Kumar, Nagi; Chornokur, Ganna (2012) Molecular Targeted Therapies Using Botanicals for Prostate Cancer Chemoprevention. Transl Med (Sunnyvale) Suppl 2:005
Connors, Shahnjayla K; Chornokur, Ganna; Kumar, Nagi B (2012) New insights into the mechanisms of green tea catechins in the chemoprevention of prostate cancer. Nutr Cancer 64:4-22
Kumar, Nagi; Crocker, Theresa; Smith, Tiffany et al. (2012) Challenges and potential solutions to meeting accrual goals in a Phase II chemoprevention trial for prostate cancer. Contemp Clin Trials 33:279-85
Kumar, Nagi; Crocker, Theresa; Smith, Tiffany et al. (2012) Prostate Cancer Chemoprevention Targeting Men with High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) and Atypical Small Acinar Proliferation (ASAP): Model for Trial Design and Outcome Measures. J Clin Trials 2:
Kumar, Nagi; Crocker, Theresa; Smith, Tiffany et al. (2012) Prostate Cancer Chemoprevention Targeting High Risk Populations: Model for Trial Design and Outcome Measures. J Cancer Sci Ther 2011: