Breaking off Cancer Cells Addiction to Prevent and Treat Recurrent Ovarian Cancer
Abstract
Understanding the pathways responsible for ovarian cancer recurrence and chemoresistance serves the two most pressing needs in the clinical management of ovarian cancer: prevent recurrence in women that are in remission and provide with effective treatment for patients that have recurred. The preponderance of evidence suggests that cancer stem cells are the progeny of cells giving rise to recurrent and chemoresistant ovarian cancer and that they do so by undergoing epithelial-to-mesenchymal transition (EMT). The Wnt/beta-catenin pathway is a key regulator of EMT and is aberrantly activated in ovarian cancer. Importantly, the deubiquitinating enzyme USP14 was recently fund to be upregulated in ovarian cancer and to act as a master regulator of the Wnt/beta-catenin pathway. Recent studies have revealed that USP14 expression in clinical specimens of ovarian cancer correlates with poorer clinical outcome. In our laboratory, we have recently shown that USP14 is an independent prognostic marker for endometrial cancer recurrence. Among endometrial cancer, serous and clear cell types are at increased risk for recurrence. Because a similar treatment algorithm is utilized among serous and clear cell endometrial and ovarian cancers, this suggests that recurrent endometrial cancer and ovarian cancer share a similar biology. We have also recently discovered that cancer cells derived from patients with recurrent and chemoresistant ovarian cancer are highly dependent upon the activity of USP14 and exquisitely sensitive to its inhibition. Importantly, USP14 is co-expressed with EMT markers during the multi-stage process, leading cancer recurrence and chemoresistance. Lastly, the first USP14 specific inhibitor VLX1570 was just Food and Drug Administration (FDA)-approved for human cancers. This renders USP14 an ideal molecular target whose inhibition can rapidly enter the clinics and radically change the management of ovarian cancer. This proposal is designed to test: (1) whether USP14 promotes and sustain ovarian cancer recurrence and chemoresistance; therefore, its aberrant expression is a "stratifying trait" of recurrent and chemoresistance ovarian cancer; (2) the mechanisms through which USP14 contributes to onset of recurrence and chemoresistance via regulating of Wnt/beta-catenin signaling pathway and EMT transition in ovarian cancer stem cells; (3) the preclinical efficacy of the FDA-approved, USP14 selective inhibitor VLX1570 in a model of ovarian cancer recurrence; and (4) the preclinical efficacy of FDA-approved, USP14 selective inhibitor VLX1570, alone or in combination with standard chemotherapy to treat chemoresistant ovarian cancer. In summary, our proposal is designed to provide with effective treatments options for ovarian cancer patients that have recurred and with measures to prevent recurrence in women that are currently in remission.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710445
Entities
People
- Martina Bazzaro
Organizations
- United States Army
- University of Minnesota