Investigating the Genetic Interactions of PAX8, a Lineage-Specific Transcription Factor in Ovarian Cancer
Assaad, Jonathan R.
2023
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Ovarian cancer has the highest mortality rate of all female cancers and an even higher recurrence rate of 85%. Current treatment methods including platinum-based chemotherapy and PARP inhibitors have significantly improved the overall cancer prognosis, but still struggle to overcome the obstacles of resistance, recurrence, and off-targeting. Development of new ovarian cancer treatment is in an area ... read moreof critical need.Our central hypothesis posits that protein druggability has been vastly underestimated and that many classes of proteins, including transcription factors, can be pharmacologically modulated with covalent small-molecule inhibitors. Cysteine druggability mapping (CDM) across many ovarian cell lines revealed PAX8 as a highly druggable transcription factor. Because PAX8 is essential to many ovarian carcinomas and their precursors but not healthy epithelial tissue, development of a PAX8 inhibitor may propose a major step forward in ovarian cancer treatment. PAX8 was not susceptible to the covalent inhibitors employed in our first small-molecule compound screen. Continuation in the development of a PAX8 inhibitors first warrants a better understanding of PAX8 in the context of ovarian cancer, as it is currently poorly understood. This paper seeks to identify genetic interactions that may compose the complex transcriptional hub of PAX8 and could help guide drug development.
Thesis (B.S.)--Tufts University, 2023.
Submitted to the Dept. of Biology.read less - ID:
- 3197z191j
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