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 an 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 druggable target for halting tumor growth (1).

“I was excited about the paper. PAX8 is a really exciting molecule, particularly as a target for high grade serous ovarian cancer,” said Joanna Burdette, a pharmaceutical scientist at the University of Illinois Chicago who was not involved in the study. “We really need a strategy to take that from being just a protein of interest … to something more clinically available.”

While PAX8 is commonly expressed in ovarian cancer tissue, clinicians use it primarily as a biomarker to track ovarian cancer cells. Its function is not well characterized, which makes it challenging to target on its own.

“If you can drug [PAX8], you sort of circumvent all the things that make all the tumors different, but they still retain that identity. And so, it's almost like trying to see if you can drug its identity,” said Ronny Drapkin, a cancer biologist at the University of Pennsylvania School of Medicine and coauthor of the study. 

Drapkin’s group purified the PAX8 protein and discovered that its binding with another transcription factor, SOX17, promoted blood vessel growth in tumors. These blood vessels are crucial for tumor expansion as they traffic in nutrients and export waste. 

When the scientists depleted SOX17 or PAX8 in cell culture and mice, they found that this transcription factor depletion suppressed capillary formation in tumors. The results suggested that small molecule therapies that inhibit the function of this duo of transcription factors may stop tumor growth in its tracks. Because PAX8 is ubiquitous throughout the reproductive epithelium, this strategy may help treat a broad range of ovarian cancers. 

While 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 that focusing on PAX8’s interaction with SOX17 could provide “a new, creative way to think about affecting the protein.” 

Moving forward, Drapkin’s group is conducting an exploratory small molecule screen to narrow down the list of specific candidates. “It's sort 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 across these tumor types,” Drapkin said. “I'm not saying it's going to usurp everything that's out there, but it could be a different angle to attack these tumors from.”

Reference 

1. Chaves-Moirera, D. et al. The transcription factor PAX8 promotes angiogenesis in ovarian cancer through interaction with SOX17. Sci Signal   15, eabm2496 (2022).