Development of Novel Therapeutics Targeting Splicing Machinery in Ovarian Cancer
thesisposted on 11.06.2014, 00:00 authored by Ahmet D. Arslan
Aberrations in alternative splicing of pre-mRNA splicing have been linked to many human malignancies, yet the mechanisms for these tumor-specific changes remain underexplored and represent a promising area for therapeutic intervention. We have reported the overexpression of a splicing factor, polypyrimidine tract-binding protein 1 (PTBP1), in ovarian tumor epithelial cells compared to matched normal controls and have further shown that PTBP1 small interfering RNA–mediated down-regulation has an antitumor effect. Coordinately, the depletion of PTBP1 expression resulted in enhanced sensitivity of ovarian tumor cells to paclitaxel and cisplatin. These data support PTBP1 as a novel target for the treatment of ovarian cancer. However, no commercially available PTBP1 inhibitors have yet been described. To expand our ability to find novel inhibitors, we developed and implemented a robust cell-based high throughput screening assay for the discovery of small molecule modulators of PTB activity. The targeting of a splicing factor, such as PTBP1, represents an innovative approach for cancer therapeutics and provides a foundation for generating new lead compounds that specifically target the PTBP1 protein to be used in ovarian cancer therapy.