A universal drug target for ovarian cancer
Ovarian cancers are genetically and morphologically diverse and can be difficult to treat. However, these diseases all have one underlying commonality: they express the transcription factor PAX8. Researchers at the University of Pennsylvania School of Medicine recently discovered a protein interaction with PAX8 that regulates blood vessel development in ovarian tumors, which may present a drug target to arrest tumor growth (1).
“I was enthusiastic about the newspaper. PAX8 is a really exciting molecule, especially as a target for high-grade serous ovarian cancer,” said Joanna Burdette, a pharmaceutical scientist at the University of Illinois at Chicago who was not involved in the study. ‘study. “We really need a strategy to move this from just a protein of interest…to something more clinically available.”
While PAX8 is commonly expressed in ovarian cancer tissue, clinicians primarily use it as a biomarker to track ovarian cancer cells. Its function is not well characterized, making it difficult to target alone.
Ronny Drapkin, a cancer biologist at the University of Pennsylvania School of Medicine, is studying signaling interactions in ovarian cancer to develop a broadly applicable treatment.
credit: Ronny Drapkin
“If you can do drugs [PAX8], you sort of bypass all the things that make all tumors different, but they still retain that identity. And so, it’s almost like trying to see if you can drug his identity,” said Ronny Drapkin, a cancer biologist at the University of Pennsylvania School of Medicine and co-author of the study.
Drapkin’s group purified the PAX8 protein and discovered that its binding to another transcription factor, SOX17, promotes the growth of blood vessels in tumors. These blood vessels are crucial for tumor expansion as they transport nutrients and export waste products.
When scientists depleted SOX17 or PAX8 in cell cultures and mice, they found that this depletion of the transcription factor suppressed capillary formation in tumors. The findings suggest that small molecule therapies that inhibit the function of this transcription factor duo could stop tumor growth in its tracks. Because PAX8 is ubiquitous in reproductive epithelium, this strategy may help treat a wide range of ovarian cancers.
Although the researchers understood that PAX8 plays a role in the aggressive nature of ovarian cancer, they didn’t know much about its regulation before this study. Burdette said focusing on the interaction of PAX8 with SOX17 could provide “a creative new way to think about affecting the protein.”
Going forward, Drapkin’s group is conducting exploratory small molecule screening to narrow the list of specific candidates. “It’s kind of satisfying in the sense that if you could find a way to disrupt a factor like [PAX8], you might be able to have a compound that would work on those types of tumors,” Drapkin said. “I’m not saying it’s going to usurp everything out there, but it could be a different angle to attack these tumors.”
- Chaves-Moirera, D. et al. The transcription factor PAX8 promotes angiogenesis in ovarian cancer by interaction with SOX17. ICS signal 15, eabm2496 (2022).