15 hours Ago By Fay Lin, PhD
In 2021, the lab of chemical biologist and Nobel Laureate Carolyn Bertozzi, PhD, professor at Stanford University, characterized a new type of cell-surface protein, termed glycoRNAs, that form highly organized clusters with RNA-binding proteins to regulate communication between cells and their environment. In a new study published in Nature Biotechnology titled “Treatment of acute myeloid leukemia models by targeting a cell-surface RNA-binding protein,” researchers from Boston Children’s Hospital, in collaboration with Cambridge (UK) Stem Cell Institute, now show that these glycoRNAs can be used to fight cancer. Led by Ryan Flynn, MD, PhD, assistant professor of stem cell and regenerative biology at Harvard Medical School (HMS), the study identified one RNA-binding protein on the cell surface, NPM1, as a potent selective target for treating acute myeloid leukemia (AML) as well as solid tumors.
“Finding cell-surface targets that are specific to malignancies but spared on healthy tissue has been a long-sought-after goal for immuno-oncology,” said Benson George, MD, PhD, a co-first author on the paper and a postdoctoral fellow in the Flynn lab. “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,” George continued.
AML is a rapidly progressive blood cancer that is difficult to target therapeutically because many of the cancer’s driving pathways are also essential for noncancerous 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,” said Flynn. Mutations in the NPM1 gene have been strongly implicated in adult AML and drive approximately 60% of cases not attributed to chromosomal abnormalities.
While NPM1 is normally found inside the cell, the HMS authors observed that leukemic cells possessed tenfold more NPM1 on the cell surface compared to healthy cells. Additionally, they observed a greater than 100-fold difference between cancerous and healthy blood stem cells. Cell-surface proteins are valuable therapeutic tools as they are easily detectable and can provide an avenue for monitoring patients.
These surface proteins can also be readily targeted with widely used agents such as antibodies. Using monoclonal antibodies to target NPM1, the researchers saw robust anti-tumor activity in multiple in vivo models of AML with minimal impact on noncancerous blood cells and stem cells. Results showed that the antibodies neutralized AML and prolonged survival in four separate mouse models of leukemia.
Notably, the antibodies effectively targeted leukemic stem cells in bone marrow samples and mouse models, which Flynn noted as “critical” because a handful of leukemia stem cells can regenerate the cancer even under the appearance of eradication. Expanding to other cancers, the authors tested dozens of human and mouse solid tumor models and found that most possessed 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.
“The development of novel cancer therapies is largely dependent on the discovery of new cancer biology,” said Konstantinos Tzelepis, PhD, a 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 the mechanism behind NPM1 surface presentation and explore whether clusters of glycoRNA and RNA-binding proteins contain other targetable molecules relevant to cancer. The post Novel Leukemia Target Found in RNA-Binding Cell Surface Protein appeared first on GEN - Genetic Engineering and Biotechnology News..
