New Combination Strategy Shows Promise in Glioblastoma Treatment

Targeting gene mutations causes stress that damages cancer cell DNA.

A new treatment strategy that targets mutations in glioblastoma cancer cells showed promise during a recent study.

Published May 5 in Oncotarget, the study examined whether a mouse model of glioblastoma and glioblastoma tissue taken from human patients before being cultured in the lab can be effectively treated through a combination of 3 anti-cancer drug classes. The combination includes a treatment that targets a cancer mutation in the Epidermal Growth Factor Receptor (EGFR) gene, a drug that increases cancer cell stress, and a drug that causes damage to cancer cell DNA.

"Developing therapies against glioblastoma is like a chess game. For each therapy administered, or move, by the physician, the cancer makes a counter-move," said senior author Clark Chen, MD, PhD, in a press release.

Nearly 50% of glioblastomas carry mutations in the EGFR gene that cause cancer cells to be insensitive to growth regulation by environmental cues, which allows for uncontrollable growth. However, highly specific EGFR inhibitors do not show efficacy against glioblastomas with EGFR mutations.

"When glioblastoma cells are treated with EGFR inhibitors, they turn on another receptor to bypass the need for EGFR," Dr. Chen said. "Any hope of an effective treatment requires a combination of moves strategically designed for a checkmate."

The researchers examined PLK1, a protein vital to cancer cell survival that regulates stress levels within glioblastoma cells. The researchers noted that glioblastoma cells that develop resistance to EGFR inhibitors are universally dependent on PLK1.

Mouse models of glioblastoma and explants of human glioblastoma found that singular treatment with the EGFR inhibitor Gefitnib, the PLK1 inhibitor BI2536, or current standard of care DNA-damaging agent TMZ can stop glioblastoma growth temporarily, but similar to the human disease, the tumor eventually grew back.

Meanwhile, when all 3 drugs were used in combination, the researchers observed no detectable evidence of tumor recurrence. The mice who received the combination tolerated the combination regimen without showing significant side effects.

While the side effects of the combination treatment on humans is unknown, individually the 3 drugs are well tolerated.

"It is often assumed that if we find the cancer-causing mutation and inhibit the function of that mutation, we will be able to cure cancer," said study co-author Bob S. Carter, MD, PhD, in a press release. "Our study demonstrates that the reality is far more complex. Our results provide a blueprint for how to leverage fundamental biologic concepts to tackle this challenging complexity."