Glioblastoma Survival Technique Provides Clues to New Treatment Strategy

Inhibiting a protein kinase may improve the efficacy of radiation in glioblastoma.

Cancer cells are constantly adapting and changing their processes in order to evade death. A new Cancer Cell study suggests that understanding how glioblastoma cells survive may lead to more effective radiation therapy.

Glioblastoma is a common and very aggressive subtype of brain cancer. Although patients are treated with surgery, radiation, and chemotherapy, there is no cure.

Prior studies show that autophagy may be triggered by cancer treatments, allowing tumors to survive and proliferate. Since drug-resistant tumors are even more difficult to combat, there has been significant interest in blocking the survival mechanism.

In the new study, the authors aimed to better comprehend what role autophagy plays in cancer. Understanding this may lead to novel treatment targets.

“Our findings solidified the concept of the promoting role of autophagy in malignant glioblastoma, and point out the necessity of specifically targeting autophagy in combination with first-line treatments—like radiation—for glioblastoma and other tumors,” said principal investigator Shi-Yuan Cheng, PhD.

The researchers first found that the MST4 protein kinase promotes tumor development in glioblastoma.

Further examination revealed that ATG4B—a substrate of MST4—allows the protein to increase autophagic activity to promote tumor growth, according to the study.

After they discovered the mechanism of MST4, they tested an inhibitor in a brain orthotopic xeno graftmodel.

When combined with radiotherapy, the drug dampened tumor growth and increased overall survival in animal models of glioblastoma, according to the study.

“We identified a pro-autophagic signaling axis in glioblastoma, whose pharmacologic inhibition enhances the anti-tumor activity of radiation,” Dr Cheng said.

These findings suggest that inhibiting MST4 may be an effective therapy for patients with glioblastoma (GBM), as it could amplify the effects of radiation therapy (RT); however, additional research is needed to confirm this effect in humans, according to the study.

“In conclusion, this study not only describes a signaling relationship by which MST4 phosphorylation of ATG4B promotes autophagy, contributes to GBM malignancy, and lessens tumor response to RT, but also reveals a clinical opportunity involving combined ATG4B inhibitor and RT for treating patients with GBM,” the authors wrote. “It will be of interest to discover whether these results are generalizable to the treatment of other cancers.”