Pax8: A Unifying Target for Serous Tumors
Abstract
Central Problem: Ovarian cancer is the fifth leading cause of cancer death in U.S. women. This is mainly due to the lack of understanding of early events in the disease, poor diagnostic biomarkers, late detection, and ineffective drug treatments. The cell of origin of ovarian cancer has been hotly debated. High-grade serous ovarian cancer (HGSOC), the most common and deadly subtype, may arise from either the ovarian surface epithelium (OSE) or the fallopian tube epithelium (FTE), with much evidence supporting both cell types. Paired-box transcription factor 8 (PAX8) is a protein involved in the differentiation of the female reproductive tract, including the fallopian tube. Therefore, PAX8 is normally abundant in the fallopian tube, but it is completely absent in the normal ovarian surface. Interestingly, 89%-100% of high-grade serous tumor samples express PAX8. Mouse models of HGSOC derived from the OSE demonstrate that the tumors can acquire PAX8 expression, suggesting that PAX8 is not only a marker of fallopian tube origin, but perhaps an essential part of HGSOC progression, potentially from both proposed progenitor cell types. Furthermore, previous studies suggested that PAX8 expression is essential for the survival of HGSOC cells because reducing PAX8 resulted in cellular death in four independent cell line models, but not in normal OSE cells or normal fallopian tube cells. Relevance to Department of Defense (DoD) Mission: The DoD is specifically interested in treatment resistance, etiology, and changes in the microenvironment. PAX8 appears to be essential for survival of HGSOC, regardless of cell of origin; combination strategies targeting PAX8 may help to provide a new treatment and could be studied in a resistant setting; and PAX8 also appears to critically regulate factors that impact angiogenesis in the tumor microenvironment. HGSOC cell lines undergo cell death when PAX8 protein expression is attenuated. Induction of cell death from PAX8 loss was not seen in any other cancer cell lines tested or in immortalized OSE cells. PAX8 is in almost all HGSOC samples, and targeting this protein may provide a unique means to slow or treat the disease. By designing a new assay and screening a library of Food and Drug Administration (FDA)-approved drugs for compounds that repress PAX8 expression, we hope to identify an ovarian cancer-specific therapeutic. We have already identified one compound, thiostrepton, which is an FDA-approved drug that reduces the expression of the PAX8 protein in multiple HGSOC cell lines. Hypothesis: We will test the hypothesis that PAX8 is an essential part of HGSOC formation from the OSE and FTE, and small molecules that reduce PAX8 expression could serve as a potential new therapy. Impact of Study: Expression of PAX8 in HGSOC is very common and may reflect the cell of origin. Alternatively, cells that become tumors from the ovarian surface may acquire PAX8 expression. If both OSE and FTE give rise to HGSOC, a clear understanding of how PAX8 expression is controlled may provide a common route of tumor formation between the two cell types. Given recent studies that suggest that silencing PAX8 can induce cell death of HGSOC cell lines of unknown origin, this target may provide a therapeutic option, regardless of cellular origin. Not only does PAX8 impact tumor cells, but it appears to play an important role in the recruitment of new blood vessels in the process of angiogenesis of the tumor, based on changes in RNA expression. Therefore, blocking PAX8 may impact the tumor cells and their ability to vascularize. Inhibiting PAX8 with small molecules that block PAX8 expression in the fallopian tube may provide new drug targets for HGSOC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710095
Entities
People
- Joanna Burdette
Organizations
- United States Army
- University of Illinois at Chicago