High-risk neuroblastoma is one of the most aggressive forms of solid tumors affecting children, originating in the nervous system. While a newer class of targeted immunotherapy drugs has improved survival rates, according to the American Cancer Society, cancer can hide from the immune system, causing patients to relapse or develop resistance to treatment. Now, a team of researchers from Penn State College of Medicine discovered a novel strategy to unmask cancer cells, improving the effectiveness of immunotherapy in cell experiments and in mouse models.
In a study published in the journal Autophagy, the researchers found that blocking a single protein, PIK3C3/VPS34, raised levels of GD2, a target molecule for neuroblastoma immunotherapy, on the surface of tumor cells. Monoclonal antibodies, which are lab-made proteins engineered to recognize and bond to a specific target, attach to GD2 on the surface of tumor cells, marking them for destruction by the patient's own immune cells. By raising the levels of GD2, the tumor cells in the study became easier to detect and more vulnerable to anti-GD2 immunotherapy. It also made the environment around the tumor more hostile to cancer growth.
The findings showed that PIK3C3/VPS34, or VPS34 for short, plays a key role in whether neuroblastoma tumors survive and respond to immunotherapy, said corresponding author Hong-Gang Wang, Lois High Berstler Professor of Pediatrics and professor of cell and biological systems at Penn State College of Medicine. He added there is a potential path to boost the effectiveness of anti-GD2 immunotherapies, such as the monoclonal antibodies dinutuximab and naxitamab, with a drug targeting VPS34, but more research is needed.
"The reality is we're trying to understand how to target neuroblastoma cells through multiple pathways to get more therapeutic benefit," Wang said. "VPS34 inhibition can enhance anti-GD2 immunotherapy, and it also independently makes the neuroblastoma tumor cells more detectable and vulnerable."
