A Bioinformatic Approach to Identify New Metabolic Targets in Prostate Cancer
C Priolo, J Lamb, G Zadra, D Oldridge, E Palescandolo, E Sicinska, M Loda. Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Broad Institute, Harvard and MIT, Cambridge, MA
Background: Cancer cells undergo fundamental changes in their metabolism, including a shift from mitochondrial respiration to a higher rate of glycolysis and an increase in de novo fatty acid synthesis. To this end, we focused our attention on the role of the metabolic enzyme Fatty Acid Synthase (FASN) as an oncogene and a potential drug target in prostate cancer (PCa), and showed that FASN overexpression is able to transform immortalized prostate epithelial cells (PrECs).
Design: We used gene microarray data and KEGG as pathway visualization tool to map metabolic changes induced by FASN during transformation of PrECs. In order to identify drugs that could contrast these metabolic effects, we applied the bioinformatic approach Connectivity Map, which uses pattern-matching tools to detect similarities between gene expression signatures of cells treated with various drugs and those obtained by overexpressing or silencing genes. We compared the transcriptome of PrEC-FASN to gene expression data from human cancer cells treated with an extensive library of compounds.
Results: FASN-driven transformation of PrECs is characterized by a remarkable increase in the expression of enzymes of glycolysis and oxidative phosphorylation, in addition to the expected lipid synthesis boost. These results suggest a global impact of FASN overexpression on the metabolism of normal as well as cancer cells. By the Connectivity Map approach, we obtained a list of 14 drugs inducing gene expression profile changes that were inversely correlated with the FASN signature, thus being potentially able to inhibit the FASN phenotype. Some of these compounds are known metabolic poisons, while others are currently in the clinic for non-tumor applications, though they were not previously known for their properties as metabolic perturbagens.
Conclusions: We mapped metabolic changes induced by FASN in prostate epithelium and identified compounds potentially able to neutralize the FASN metabolic phenotype. Pre-clinical validation of these compounds is ongoing.
Category: Special Category for 2009 - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 10, 2009 9:30 AM
Poster Session III # 234, Tuesday Morning