Chemoprevention of Prostate Cancer, HDAC Inhibition and DNA Methylation

• Identify distribution of SFN (sulforaphane) and its metabolites and HDAC (histone deacetylase) inhibition following SFN supplementation [ Time Frame: minimum 4 to maximum 8 weeks ] [ Designated as safety issue: No ]
  In subjects at risk for prostate cancer by examining expression of acetylated H3 and H4, and absolute histone levels in peripheral blood and in prostate tissue. Presence of SFN and its metabolites (SFN-Cys, SFN-NAC) will be analyzed in plasma, urine and prostate tissue. Collection of blood and urine specimens will occur at pre-intervention and post-intervention; research only prostate biopsy specimens will be collected post-intervention at the time of the clinically-indicated prostate biopsy.
  
  

• Investigate the effects (biomarkers of disease progression) of broccoli sprout supplementation on DNA methylation status and proliferation markers in a pre-biopsy setting. [ Time Frame: minimum 4 to maximum 8 weeks; prostate biopsy will be collected post-intervention when clinically-indicated ] [ Designated as safety issue: No ]
  Prostate biopsy samples will be probed for 5-methyl cytosine staining by IHC; and serum and urinary DNA will undergo methyl-specific PCR for GSTp1, AR, sigma14-3-3 and P21. Cell proliferation (Ki-67 expression) and apoptosis (TUNEL expression) in SFN-supplemented and placebo prostate tissue specimens will be assessed. Collection of blood and urine specimens will occur pre-intervention and post-intervention; research only prostate biopsy specimens will be collected post-intervention at the time of the clinically-indicated prostate biopsy.
  
  

Prostate cancer is the most frequently diagnosed non-cutaneous cancer and is the second leading cause of cancer death in American men. The precise etiologic factors that initiate and enhance the progression of prostate cancer remain unknown, but epigenetic alterations and diet/lifestyle factors have come forth as significant contributing factors. Epidemiologic studies suggest that cruciferous vegetable intake decreases the risk for prostate cancer. The long-term goal of this proposal is to identify mechanisms by which dietary compounds, such as those found in cruciferous vegetables decrease prostate cancer risk. The objective of the study is to identify mechanisms by which compounds found in cruciferous vegetables alter gene expression via epigenetic modifications and may prevent prostate cancer development.

The investigators have found that SFN, an isothiocyanate found in cruciferous vegetables, inhibits HDAC activity in human colorectal and prostate cancer cells.

Targeting the epigenome, including the use of HDAC and DNA methyltransferase (DNMT) inhibitors, is an evolving strategy for cancer chemoprevention and both have shown promise in cancer clinical trials.

This Randomized, Double Blind, Clinical Trial will address the following objectives:

1. Identify distribution of SFN and its metabolites and HDAC inhibition following SFN supplementation in subjects at risk for prostate cancer (Primary Endpoints)
2. Investigate the effects of broccoli sprout supplementation on DNA methylation status and proliferation markers in a pre-biopsy setting (secondary analysis)

The effects of short-term SFN supplementation on benign epithelial tissue will be studied in men characterized as being at risk for prostate cancer in a randomized, placebo-controlled trial. Men scheduled for prostate biopsy will be recruited into the trial.

Following successful completion of the consent, two 10 mL blood specimens for study analyses, a 4 mL specimen for total bilirubin assessment will be drawn and the subject will provide a urine sample. The study coordinator will explain the Diet History questionnaires (DHQ) and administer the risk factor and adverse event (AE) questionnaires in order to obtain data on potential confounding dietary variables and gain subjects' baseline symptoms.

The study coordinator will provide the subject with a four-week supply of either SFN glucosinolate capsules or matching placebo, as dispensed by the Research Pharmacy.

Around every 2 weeks, study coordinator will call to complete AE reporting and any changes in medications or supplements and complete brief cruciferous vegetable intake checklist. Subjects will return any unused study "drug" to the study coordinator at the time of biopsy (or at the 4 week visit if subject's prostate biopsy is delayed).