Targeting TMPRSS2-ERG in Prostate Cancer
Technical Report,01 Sep 2013,31 Aug 2014
Dana-Farber Cancer Institute Boston United States
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Approximately half of all prostate cancers are known to harbor the TMPRSS2-ERG translocation resulting in aberrant ERG expression that contributes to prostate tumorigenesis. Despite being an attractive therapeutic target, transcription factors such as ERG have been historically difficult targets for drug development. To address these challenges, we developed a method to measure gene expression patterns in a high throughput format and generated a gene signature that differentiates between cells that have active TMPRSS2-ERG activity versus cells in which its activity is suppressed. Using this technique we measured the effect of inhibiting 800 kinases by RNAi on ERG activity in prostate cancer cells to identify kinases that modulate ERG activity. To identify novel small molecules that directly bind to an inhibit ERG activity we tested 100,000 compounds using a recently developed technique of drug screening called small molecule microarrays. The identified compounds were subsequently tested in our gene signature assay to discover novel compounds that inhibit ERG activity in prostate cancer cells. We have also used our gene expression method to test a panel of commercially available and FDA approved drugs and identified multiple drugs that inhibit ERG activity.