For decades, cancer researchers have faced a frustrating reality: some of the molecules that fuel cancer are among the most important targets to stop, yet nearly impossible to drug. One of them is FXR1, a protein that helps tumors survive, spread, and resist treatment.
A promising new therapy developed by investigators in the laboratory of Pradeep Chaluvally-Raghavan, PhD, may offer a way to shut down FXR1 at its source. In ovarian cancer models, the RNA-based treatment slowed tumor growth, reduced the spread of disease, and helped activate immune cells that can recognize and attack tumors. Importantly, it selectively targeted cancer cells while largely sparing healthy ones, a key step toward safer treatments. These results were recently published in Nature Communications.
“We’ve spent years studying how FXR1 helps cancer cells grow and spread. What makes this work exciting is that we were able to move beyond understanding the biology and develop a strategy to target it,” said Jasmine George, PhD, research scientist, Chaluvally-Raghavan Lab, first author of the study.
The findings could have implications not only for ovarian cancer, but also for other cancers where FXR1 is overexpressed, including endometrial, lung, cervical, and head and neck cancers. More broadly, this work suggests that proteins once considered impossible to drug may represent some of the next frontiers in cancer therapy.
The Ripple Effect of Silencing FXR1
The study builds on years of research from the Chaluvally-Raghavan lab investigating FXR1 and its role in ovarian cancer. To switch off the protein, the team developed a specialized form of small interfering RNA (siRNA), a therapy that uses small pieces of genetic material to prevent cancer cells from producing specific proteins. The treatment incorporates locked nucleic acid (LNA) modifications that improve stability and help it reach tumor cells more effectively.
After seeing promising results in ovarian cancer models, the team wanted to better understand exactly how the therapy was working. They turned to single-cell RNA sequencing, a powerful technology that allowed them to examine thousands of individual tumor and immune cells and track how different cell populations responded to treatment.
“One of the biggest challenges in developing RNA-based therapies is understanding how they affect the many different cell types within a tumor. Using single-cell sequencing, we were able to see the therapy’s effects across the entire tumor ecosystem. What we found was very encouraging,” said Pradeep Chaluvally-Raghavan.
The analysis revealed fewer tumor-promoting immune cells and an increase in several types of cancer-fighting immune cells, including T cells, natural killer cells, and dendritic cells. Just as importantly, the researchers were able to see how the therapy affected every major cell type within the tumor, including cancer, immune, and supportive stromal cells.
This level of detail is rarely available when evaluating RNA-based cancer therapies, Dr. Chaluvally-Raghavan explained. The findings provided important insight into the treatment’s specificity and how different cell populations responded to FXR1 silencing.
The study also supported by the Cancer Center’s Biorepository and Tissue Analytics Shared Resource, one of several resources that help investigators access specialized expertise and technologies needed to advance cancer research.
From Trainee to First Author
The publication also marks a major milestone for Dr. George, who joined MCW as a postdoctoral fellow in 2018 and has spent nearly eight years helping advance the laboratory’s understanding of FXR1 and its role in cancer.
“My experience as a trainee and now as a research scientist in the same lab has been incredibly rewarding,” said Dr. George. “The support I received through the MCW Cancer Center and the collaborations it fostered helped take both this research and my career to the next level.”
For Chaluvally-Raghavan, helping trainees grow into independent scientists is just as important as the discoveries themselves. “I encourage trainees to pursue ambitious questions and take ownership of their ideas, while also recognizing when collaboration can accelerate progress,” he said.
“No one person can be an expert in every aspect of a project. The most impactful science happens when talented people with different expertise come together to solve important problems,” said Chaluvally-Raghavan.
Looking ahead, the team is working to advance the patented therapy toward clinical development and further improve precision by linking it to tumor-targeting antibodies. Because FXR1 is overexpressed in multiple cancer types, the researchers believe the approach could serve as a blueprint for targeting cancer-driving proteins once considered out of reach.