Joyce Ohiri

Transcription factors have been known to be undruggable targets. Yet, in identifying small-molecule inhibitors of E26 Regulated Gene (ERG), a transcription factor, in prostate cancer, we plan to revolutionize this concept using a three-pronged synergistic approach. Using shRNAs to test their codependency with ERG, diversity-oriented synthesis (DOS) compounds for new structure space, and a small molecule microarray to identify direct binders to ERG, we hope to identify new therapies for prostate cancer. Initiating nearly half of prostate cancer cases, a translocation on chromosome 21 occurs in which the 5’ untranslated region of Transmembrane Protease, Serine 2 (TMPRSS2), an androgen-regulated gene, fuses with the translated region of ERG. Due to this fusion, ERG is now activated by androgen, which consequentially over-expresses this protein. Since ERG is involved in many diverse regulatory pathways that induce tumorigenesis, we used a Gene Expression-Based High-Throughput Signature Screen (GE-HTS) to determine the pathway of ERG and the function of the TMPRSS2-ERG fusion in prostate cancer. We suppressed 4,000 kinases and screened 10,000 DOS compounds (from a diverse chemical library of unique structures) hoping to find treatments that match the gene signature of the inactivation or silencing of ERG. We used a Luminex bead-based signature assay to generate gene signatures from these treatments and compared their enrichment scores to that of our desired gene signature. In our invasion assay, we tested the effects of ERG on the invasiveness of prostate cancer cells in vitro. Using different cell lines, different types of chemoattractants, and different time points, we have optimized invasive conditions for the VCaP cell line and identified compounds that silence ERG. The prospective drugs will be analyzed to determine whether they can prevent prostate cancer cells from invading in vivo and reaching other areas of the body. We will test these molecules in various secondary assays to see if they inhibit ERG and to determine their functional properties (e.g. invasion, transformation, proliferation, and epithelial mesenchymal transition, or EMT). GE-HTS will not only serve as a novel method for drug synthesis, but it will also act as a universal system in identifying therapeutic agents for transcription factors.

 

PROJECT: Identifying Small-Molecule Inhibitors of ERG in Prostate Cancer

Mentor: David Takeda, Cancer Program

Joyce Ohiri

"My experience at the Broad was dynamic in all dimensions. The breadth of creativity and collaboration will capture you. The Broad is special and having the opportunity to conduct phenomenal research here was certainly unforgettable!"