A study led by UT Southwestern researchers indicates that the sequence in which certain drugs are administered could significantly impact the effectiveness of glioblastoma treatment. The research suggests that giving an EGFR inhibitor prior to the chemotherapy drug temozolomide may help overcome resistance mechanisms in the aggressive brain cancer.
Glioblastoma remains one of the most fatal primary brain cancers in adults, with median survival rates hovering around 15 months despite standard treatments involving surgery, radiation, and temozolomide. The disease affects approximately 14,000 Americans annually and has historically resisted major therapeutic advances.
The investigation focused on MGMT, a DNA repair enzyme that allows glioblastoma cells to reverse the damage caused by temozolomide, thereby enabling the cancer to survive chemotherapy. The team discovered that EGFR signaling within these tumor cells drives the production of MGMT. By applying an EGFR inhibitor first, the study found that EGFR signaling is shut down, which reduces MGMT levels.
This suppression leaves the tumor cells unable to repair the DNA damage inflicted by subsequent temozolomide doses, making them far more sensitive to the chemotherapy.
Crucially, the timing of the drug administration proved vital. The researchers observed that delivering the EGFR inhibitor and temozolomide simultaneously did not produce the sensitization effect. Only the sequential approach, where the EGFR inhibitor is given first to suppress MGMT, yielded the benefit.
This finding helps explain why previous clinical trials combining these drugs failed; those studies administered both agents at the same time, never allowing the window for MGMT suppression to open before chemotherapy was introduced.
The team tested the EGFR inhibitor afatinib, which is already approved for treating non-small cell lung cancer. They found that afatinib sensitized both glioblastoma cell lines and mouse tumor models to temozolomide, even in cases where the tumors had already developed resistance to the chemotherapy.
Dr. Amyn Habib, a professor of neurology and neurological surgery at UT Southwestern and staff physician at the Dallas Veterans Affairs Medical Center, highlighted the potential impact of these findings. "Glioblastoma is a devastating brain cancer with a dismal prognosis and no truly effective treatments. Our study could give new hope to the approximately 250,000 patients worldwide diagnosed with this disease each year," Habib said.
