Project Number: 5306-51530-014-00
Project Type: Appropriated

Start Date: Oct 20, 2004
End Date: Apr 30, 2009

Objective:
Our primary objective is to define the critical biochemical and genetic mechanisms that influence prostate cancer progression and its reduction by selenium, lycopene and zinc. Our specific objectives are as follows. 1) To investigate the biological processes and molecular mechanisms underlying the cancer-protective actions of lycopene, selenium, and zinc in normal and cancerous human prostate epithelial cell lines. 2) To test the mechanisms of zinc, selenium, and lycopene identified in the literature or predicted from our cell-line studies in Objective 1 in nude mice transplanted with human prostate cancer cells to identify the best combination of zinc, selenium and lycopene concentrations that inhibits prostate cancer progression in mice. In addition, to test mouse serum for biomarkers for prostate cancer predicted from cell studies in Objective 1 or through literature review. 3) To test the best combination of selenium, lycopene and zinc identified in nude mice in Objective 2, for its ability to retard or reverse the progression of pre-cancerous lesions and candidate biomarkers in men with elevated PSA (prostate specific antigen).

Approach:
We will be using the same cell-lines, animal models, and human populations for our studies of zinc, selenium, and lycopene. The cell lines will be the normal prostate epithelial cell line RWPE1 and its cancerous twin RWPE2. Our rodent model will be the scid (severe combined immune deficiency, C57BL/6J-Prkdcscid/SzJ) mouse. We will recruit humans for our final test from the Greater Sacramento Area of California, identified as the most diverse community in the United States. We will use Hu-133a GeneChips gene expression profiling to identify mechanisms by which zinc, selenium and lycopene inhibit prostate cancer progression in RWPE1 and RWPE2 cell lines. We will compare the gene expression profile of RWPE1 to RWPE2 to identify genes associated with cancer, and compare differences in gene expression that occur with different concentrations of nutrient. We will then map our lists of micronutrient-regulated, malignancy-associated genes using GenMAPP software to identify genes and genetic products that we will use as markers of cancer progression and nutrient effectiveness in our animal and human studies. We will determine the effectiveness of different concentrations of single and combined nutrients against prostate cancer in nude mice. Selenium, zinc, and lycopene appear to inhibit prostate cancer progression by interactions with different metabolic and genetic pathways, so combined interventions should be more effective then single nutrient interventions. We will then test the most effective combinations of micronutrients found in our nude mouse studies in humans. We will feed human volunteers with high levels of prostate specific antigen the combination of selenium, lycopene and zinc whose concentration is extrapolated from the combination of these nutrients that gave the best results for inhibiting prostate cancer progression in nude mice, for six months. Biopsy samples will be analyzed for cancer blind, so that the evaluator does not know which sample was collected before, and which after, our nutritional treatment. We will test for the effectiveness of the combined nutrient treatments by looking for genetic differences before and after treatment using HG-133 GeneChips, and changes in indices of cancer progression such as changes in prostate specific antigen concentrations.