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Targeting TMPRSS2-ERG in Prostate Cancer
Technical Report,01 Sep 2013,31 Aug 2017
Dana-Farber Cancer Institute Boston United States
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TMPRSS2-ERG is an oncogenic translocation present in approximately half of all prostate cancers that contributes to tumorigenesis. Despite being an attractive therapeutic target, transcription factors have historically been difficult to target pharmacologically. Furthermore, the exact role of ERG in mediating tumorigenesis is unknown making it difficult to develop physiologically relevant assays to measure its activity. To address these challenges, we developed a gene expression signature for ERG activity that provides a readout for ERG activity. Using a novel bead based assay to measure gene expression in a high throughput format, we used the ERG gene signature to screen a RNAi kinome library to identify kinases that modulate ERG activity. To identify novel small molecules that directly bind to and inhibit ERG, we tested 100,000 compounds using small molecule microarrays. The identified compounds were subsequently tested using our gene signature assay to discover novel compounds that inhibit ERG activity. Using our high throughput gene expression screening method, we identified a novel small molecule that inhibits the proliferation of prostate cancer cells with an ERG translocation. We identified the cellular target of the small molecule as p300CBP and demonstrated that it functions as a novel inhibitor of p300CBP enzymatic activity.
APPROVED FOR PUBLIC RELEASE