Evaluating the Mechanism and Therapeutic Potential of PTC-028, a Novel Inhibitor of BMI-1 Function in Ovarian Cancer

  • Mol Cancer Ther. 2018 Jan;17(1):39-49. doi: 10.1158/1535-7163.MCT-17-0574.
Anindya Dey  1 ,  Xunhao Xiong  2 ,  Aleia Crim  1 ,  Shailendra Kumar Dhar Dwivedi  1 ,  Soumyajit Banerjee Mustafi  1 ,  Priyabrata Mukherjee  2 ,  Liangxian Cao  3 ,  Nadiya Sydorenko  3 ,  Ramil Baiazitov  3 ,  Young-Choon Moon  3 ,  Melissa Dumble  3 ,  Thomas Davis  3 ,  Resham Bhattacharya  4  5
Affiliations
  • 1. Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • 2. Department of Pathology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • 3. PTC Therapeutics, South Plainfield, New Jersey.
  • 4. Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. [email protected].
  • 5. Department of Cell Biology, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma.
PMID: 29158468 DOI: 10.1158/1535-7163.MCT-17-0574
Abstract

BMI-1, also known as a stem cell factor, is frequently upregulated in several malignancies. Elevated expression of BMI-1 correlates with poor prognosis and is therefore considered a viable therapeutic target in a number of malignancies including ovarian Cancer. Realizing the immense pathologic significance of BMI-1, small-molecule inhibitors against BMI-1 are recently being developed. In this study, we functionally characterize PTC-028, an orally bioavailable compound that decreases BMI-1 levels by posttranslational modification. We report that PTC-028 treatment selectively inhibits Cancer cells in clonal growth and viability assays, whereas normal cells remain unaffected. Mechanistically, hyperphosphorylation-mediated depletion of cellular BMI-1 by PTC-028 coupled with a concurrent temporal decrease in ATP and a compromised mitochondrial redox balance potentiates caspase-dependent Apoptosis. In vivo, orally administered PTC-028, as a single agent, exhibits significant antitumor activity comparable with the standard cisplatin/paclitaxel therapy in an orthotopic mouse model of ovarian Cancer. Thus, PTC-028 has the potential to be used as an effective therapeutic agent in patients with epithelial ovarian Cancer, where treatment options are limited. Mol Cancer Ther; 17(1); 39-49. ©2017 AACR.

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