Scientific Premise and Hypothesis: Chemoprevention using safe and inexpensive phytochemicals from edible or medicinal plants is appealing for reducing the death and suffering from prostate cancer, which continues to be a leading cause of cancer-linked mortality among American men. A chemopreventative intervention for prostate cancer is still lacking. Increased de novo synthesis coupled with ?-oxidation of fatty acids is a rather unique and targetable mechanism of human prostate cancer. A role for upregulated de novo fatty acid synthesis in pathogenesis of prostate cancer is substantiated by studies showing overexpression of mRNA/protein levels of key fatty acid synthesis enzymes, including ATP citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), and/or fatty acid synthase (FASN) in early (prostatic intraepitheilial neoplasia; PIN) as well as advanced (adenocarcinoma) disease when compared to normal tissue. In addition, genetic or pharmacological suppression of ACLY, ACC1, and FASN causes inhibition of prostate cancer cell growth in vitro and in vivo. Therefore, inhibition of synthesis and/or ?-oxidation of fatty acids represents a promising strategy for chemoprevention of prostate cancer. The overall goal of this bench-cage-bedside project is to determine the feasibility of fatty acid metabolism inhibition for chemoprevention of prostate cancer using sulforaphane (SFN), which is the principal bioactive phytochemical in broccoli sprout extract (BSE). The preclinical studies are conceived to test the hypothesis that prostate cancer chemoprevention by SFN and BSE in a clinically-relevant transgenic mouse model (Hi-Myc) is associated with suppression of synthesis as well as ?-oxidation of fatty acids leading to inhibition of cancer cell proliferation. A pilot double-blind, randomized, and placebo-controlled window of opportunity clinical trial in men scheduled for prostatectomy is also proposed to determine whether daily oral administration of a well-characterized BSE formulation (BroccoMax), the safety of which has already been tested clinically, for 4 weeks leads to suppression of circulating and prostate tumor levels of fatty acids. Support for the above stated hypothesis derives from our own published and preliminary unpublished findings. Specifically, we found that SFN treatment not only suppresses protein/mRNA levels of ACC1 and FASN as well as the dehydrogenases implicated in ?-oxidation of fatty acids but also decreases acetyl-CoA levels in human prostate cancer cells in vitro and prostate tumors of TRAMP mice in vivo. Acetyl-CoA is the building block of de novo fatty acid synthesis but is also generated in the mitochondria upon ?-oxidation of fatty acids.
Specific Aims : The well-integrated specific aims of this highly-focused application are to: (1) Determine the mechanism underlying SFN-mediated inhibition of fatty acid synthesis and ?-oxidation using cellular models of prostate cancer and normal prostate cells; (2) Determine whether prostate cancer chemoprevention by SFN and BSE in Hi-Myc transgenic mice is associated with inhibition of fatty acid synthesis and ?-oxidation; and (3) Determine whether daily oral BroccoMax administration for 4 weeks decreases circulating and prostate tumor levels of fatty acids through a pilot double-blind, randomized, and placebo-controlled window of opportunity trial in men scheduled for prostatectomy. Translational Impact (Significance): Despite wealth of mechanistic data, clinical development of SFN or BSE like BroccoMax for chemoprevention of prostate cancer is contingent upon: (a) demonstration of chemopreventive efficacy in a clinically-relevant rodent model of prostate cancer; (b) identification of pharmacodynamic biomarker(s) using cellular and preclinical rodent models of prostate cancer; and (c) pilot clinical translational studies to demonstrate modulation of the same mechanistic biomarker(s) identified from the cellular/preclinical models such as suppression of fatty acid metabolism hypothesized in this application. This stepwise progression of research is essential to justify a larger clinical study with prostate cancer incidence as the primary end point. The first two specific aims of this project will not only test the possibility of prostate cancer chemoprevention by SFN and BSE in a transgenic mouse model with strong molecular overlap with the human disease but will also identify non-invasive pharmacodynamic biomarker(s) (e.g., serum levels of fatty acids) applicable to the proposed clinical trial in specific aim 3.
Increased de novo synthesis coupled with ?-oxidation of fatty acids is a rather unique and targetable mechanism of human prostate cancer. The overall goal of this bench-cage-bedside project is to determine the feasibility of fatty acid metabolism inhibition by sulforaphane (SFN), which is the principal bioactive phytochemical in broccoli sprout extract (BSE). The preclinical studies are conceived to test the hypothesis that prostate cancer chemoprevention by SFN and BSE in a clinically-relevant transgenic mouse model (Hi-Myc) is associated with suppression of synthesis and/or ?-oxidation of fatty acids leading to inhibition of prostate cancer cell proliferation. A pilot double-blind, randomized, and placebo-controlled window of opportunity trial in men scheduled for prostatectomy is also designed to determine whether daily oral administration of a well-characterized BSE formulation (BroccoMax) for 4 weeks leads to suppression of circulating (serum) and prostate tumor levels of fatty acids. Positive outcome of the studies proposed in this application would lay the foundation for a larger clinical study with prostate cancer incidence as the primary end point.
