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A new druggable cancer target: RNA-binding proteins on the cell surface

2025-04-23
(Press-News.org) In 2021, research led by Ryan Flynn, MD, PhD, and his mentor, Nobel laureate Carolyn Bertozzi, PhD, opened a new chapter in biology, characterizing a new kind of player on the cell surface: glycoRNAs. Extending this discovery recently in Cell, Flynn and colleagues showed that glycoRNAs form highly organized clusters with RNA-binding proteins on the cell surface. These clusters appear to regulate communication between cells and their environment.

Now, reporting in Nature Biotechnology, Flynn’s team in the Stem Cell Program at Boston Children’s Hospital and Dana-Farber/Boston Children's Cancer and Blood Disorders Center demonstrate a first application of this newfound biology: fighting cancer.

With collaborators at the Cambridge (UK) Stem Cell Institute, led by Konstantinos Tzelepis, PhD, and Maria Eleftheriou, PhD, they show that one RNA-binding protein on the cell surface, NPM1, could be a potent, selective target for treating acute myeloid leukemia (AML), as well as solid tumors.

 

Targeting the NPM1 protein

AML, a rapidly progressive blood cancer, has been difficult to target therapeutically because many of its driving pathways are also essential for non-cancerous cells, including blood stem cells. “The disease may be insensitive to existing drugs, or patients may be too frail to get classical therapeutics, because the toxicity is too high,” says Flynn.

He and his colleagues zeroed in on NPM1 because mutations in the NPM1 gene have been strongly implicated in adult AML — driving about 60 percent of cases not attributed to chromosomal abnormalities. While NPM1 is normally found inside the cell, Flynn, Tzelepis, and colleagues showed that in malignant AML cells, it is presented on the surface.

“The amount of cell-surface NPM1 was more than ten times higher on leukemic cells as compared to healthy cells,” says Flynn. “It was very strongly expressed on cells from nearly every patient we looked at. There was more than a 100-fold difference between cancerous and healthy blood stem cells; normal blood stem cells have almost no NPM1 on their surface.”

Because it’s a surface marker, NPM1 is easily detectable with simple methods, and could provide a way to monitor patients. But the real beauty of NPM1 being on the cell surface is that it can be readily targeted with widely used agents such as antibodies.

Using a monoclonal antibody targeting NPM1, the researchers saw robust anti-tumor activity in multiple in vivo models of AML, while noncancerous blood cells and stem cells were spared. In four separate mouse models of leukemia, the antibodies neutralized AML and prolonged survival, with no apparent toxicity.

Most excitingly, the antibodies effectively targeted leukemic stem cells in bone marrow samples and mouse models. “This is critical, because a handful of leukemia stem cells can regenerate the cancer even if it appears to be eradicated,” says Flynn.

 

What about other cancers?

The potential benefits of targeting NPM1 could extend to other cancers. The team tested 47 human and mouse solid tumor models and found that most had cell-surface NPM1 to varying degrees. Experiments in mice suggested that monoclonal antibodies targeting cell-surface NPM1 might be effective against certain solid tumors, including prostate and colorectal cancer.

“Finding cell-surface targets that are specific to malignancies but spared on healthy tissue has been a long sought-after goal for immuno-oncology,” says Benson George, MD, PhD, in the Flynn Lab, who was co-first author on the new paper with Eleftheriou. “Many cancers lack known molecular handles that can safely be leveraged to signal the immune system to attack. A great example of this is colorectal cancer, which has a rising incidence.”

“The development of novel cancer therapies is largely dependent on the discovery of new cancer biology," says Konstantinos Tzelepis, collaborator at the Cambridge (UK) Stem Cell Institute. "I am very pleased that our collaborative work has led to the discovery of a promising biotechnology approach to targeting cancers of unmet medical need. Our aim is to better understand and expedite the translation of these novel antigens into new effective treatments.”

In future work, the team plans to investigate why cells are bringing NPM1 to the surface, and to explore whether clusters of glycoRNA and RNA-binding proteins contain other targetable molecules relevant to cancer.

“We hypothesize that bringing NPM1 to the cell surface is somehow beneficial for the tumor,” Flynn says. “This is really a new class of tumor antigens.”

 

Boston Children’s Hospital has filed patent applications to protect this invention in the U.S. and foreign jurisdictions. Contact TIDO@childrens.harvard.edu for further information.

END


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[Press-News.org] A new druggable cancer target: RNA-binding proteins on the cell surface