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Development of Novel Therapeutics Targeting Splicing Machinery in Ovarian Cancer

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thesis
posted on 11.06.2014, 00:00 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.

History

Advisor

Beck, William T.

Department

Biopharmaceutical Sciences

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Committee Member

He, Xiaolong Mo, Yin-Yuan Rong, Lijun Wang, Zaijie J.

Submitted date

2012-08

Language

en

Issue date

10/12/2012