UPMC Children’s/University of Pittsburgh Study Finds Potential New Therapeutic Target for Diffuse Midline Glioma

Researchers from the University of Pittsburgh, UPMC Children’s Hospital of Pittsburgh, and several other institutions have identified a potential new therapeutic target for treating diffuse midline gliomas (DMG), highly aggressive pediatric brain tumors, including diffuse intrinsic pontine glioma, that currently have limited treatment options, dismal prognosis, and have nearly 100% mortality within five years of diagnosis.

The study, titled “An ERK5-PFKFB3 Axis Regulates Glycolysis and Represents a Therapeutic Vulnerability in Pediatric Diffuse Midline Glioma,”  was published in Cell Reports in January 2024.

Sameer Agnihotri, PhD, associate professor of Neurosurgery at the University of Pittsburgh, who directs the Brain Tumor Biology and Therapy Lab at UPMC Children’s was the study’s senior and corresponding author.

“We just don’t have a lot of options to deal with tumors right now,” says Dr. Agnihotri. “Their diffuse nature and presence in and around the brainstem take away surgical resection as an option in most instances. Finding new therapeutic targets that can attack these tumors effectively is needed.”

About the Study and its Findings

DMG tumors, driven by a specific histone mutation (H3K27M), are known for their aggressive nature. The study found that ERK5, a protein involved in cell signaling, regulates a key enzyme called PFKFB3, which is necessary for glycolysis — the process by which cells convert glucose into useable energy. Through this regulation, ERK5 enables a tumor's rapid growth.

By blocking ERK5 or PFKFB3, the research team was able to show a significantly slower tumor metabolism and growth in both cell cultures and in animal models.

Inhibiting ERK5 led to a decrease in glycolytic activity and tumor cell proliferation. Similarly, targeting PFKFB3 produced comparable results, highlighting its essential role in the tumor’s metabolic processes.

The study also explored the potential of combining both inhibitors, which showed even greater effects. This dual approach not only reduced tumor cell viability but also increased cell death and disrupted the tumor’s metabolic balance, suggesting a potential powerful strategy for tackling these resilient tumors.

“We may be able in the future to translate these findings into a therapeutic option against DMG,” says Dr. Agnihotri. “But DMG is challenging to treat for a reason, so figuring out how to move this research forward to create a new efficacious therapy will require a lot of work.”

Read the complete study using the link below to the open access publication.

Reference

Casillo SM, Gatesman TA, Chilukuri A, et al. An ERK5-PFKFB3 Axis Regulates Glycolysis and Represents a Therapeutic Vulnerability in Pediatric Diffuse Midline Glioma, Cell Reports. 2024 Jan 23; 43(1): 113557.