Genetic screens point to NXT1 as a promising target for new pediatric cancer drugs.
Researchers find genetic vulnerability in pediatric neuroblastoma
With few targeted therapies available, children with cancer often receive treatments that kill cancer and noncancer cells alike, causing many side effects. To pave the way toward more targeted drugs for childhood cancers, researchers at the Broad Institute of MIT and Harvard, Dana-Farber Cancer Institute and Boston Children’s Hospital have been looking for genes that pediatric cancer cells depend on for their growth and survival. Those genes, or dependencies, recently outlined in a dependency map for pediatric cancers, can help scientists find potential new therapeutic targets.
Now scientists from the Cancer Dependency Map (DepMap) project and their colleagues have used that map to identify one such genetic dependency—a gene called NXT1—in neuroblastoma, one of the most common solid tumors in children. In a new study published in Cancer Discovery, the scientists report that NXT1 is a promising drug target for some forms of neuroblastoma. They found that depleting NXT1 in these cancer cells results in the loss of another gene, called NXF1, which is essential for cell survival.
The researchers say drugs designed to block NXT1 could selectively kill neuroblastoma cells compared to normal cells. They have started working with colleagues in Broad’s Center for the Development of Therapeutics to look for small molecules that could inhibit NXT1. With an FDA-approved drug targeting similar cellular functions already on the market, the scientists say they are optimistic about the prospects of more targeted therapies for neuroblastoma.
“We are hopeful that targeting NXT1 will lead to a much better therapeutic window,” said Kimberly Stegmaier, senior author of the paper, an institute member and pediatric oncologist with the Cancer Program at the Broad Institute, and the vice chair of pediatric oncology research at the Dana-Farber Cancer Institute.
From DepMap to target
The team began by analyzing the pediatric dependency map they had developed, which yielded many potential drug targets. In this study, the researchers focused on one of the most common types of pediatric neuroblastomas, called MYCN-amplified neuroblastoma, which often has a poor prognosis. They found 197 possible genetic dependencies.
The scientists, including collaborators with the Genetic Perturbation Platform, then used four different CRISPR-based screens as well as several other assays to home in on dependencies that, if targeted with drugs, could lead to cancer cell death, not just reduced cell growth. NXT1 soon rose to the top of their list as a promising drug target, and also one that is found more commonly in pediatric cancers rather than in adult ones.
“This story would have been impossible without the Pediatric Cancer Dependency Map,” said Clare Malone, first author of the paper and a postdoctoral fellow at Broad and the Dana-Farber Cancer Institute.
“We can use these large-scale datasets to start understanding ways to specifically target the cancer cells, in addition to understanding which genes are essential,” said Francisca Vazquez, DepMap's scientific director at the Broad and an author of the study.
In further experiments, the scientists confirmed that NXT1 binds with and stabilizes the essential protein NXF1—the two work together to help export mRNA out of the nucleus.
The team was surprised to find that NXT1 and its close relative, or paralog, NXT2, both need to be inhibited to eliminate NXF1 and kill cancer cells. The authors suggest that there might be other paralogs that could be targeted in a similar way to inactivate an essential gene specifically in cancer cells.
“It's a new twist on how we've been thinking about finding dependencies,” said Stegmaier. “You can imagine there might be a broader mechanism beyond just NXT1 and NXT2. Are there other paralogs that partner with a target that's essential in all cells?”
The study also lays out a framework for researchers to mine genetic dependency data for potential drug targets, said Malone, a postdoc in Stegmaier’s lab. “I hope we built a road map that shows some next steps to take when you're presented with dozens of potential dependencies for a disease.”
Support for this research was provided in part by the National Cancer Institute, St. Baldrick’s Foundation Robert J. Arceci Innovation Award, Friends for Life, and the Slim Initiative in Genomic Medicine for the Americas, a joint U.S-Mexico project funded by the Carlos Slim Foundation, and Walter and Marina Bornhorst.