Timing Affects Efficacy of Glioblastoma Chemotherapy

Chronochemotherapy plus an p38 MAPK inhibitor may reduce the aggressiveness of glioblastoma cells.

The circadian rhythm tells the body when it is time to sleep and plays a significant role in countless biological processes. Research suggests that alterations in the biological clock can impact overall health and may put individuals at a higher risk for diseases such as cancer.

A study recently published by BMC Cancer suggests that circadian rhythm can be harnessed to amplify the efficacy of glioblastoma treatment.

The study authors found that the production of a protein involved with tumor proliferation is disrupted in glioblastoma cells. Harnessing this finding may lead to more effective therapies that target brain cancer cells, while sparing healthy cells, according to the study.

In their previous research, the authors discovered that the circadian rhythm of Neurospora crassa controls the daily rhythm in the activity of p38 mitogen activated protein kinase (MAPK), which is a signaling protein that contributes to glioblastoma’s aggressive nature.

The current study demonstrated that the biological clock controls daily rhythms in p38 MAPK activity in mammalian cells, including healthy glial cells.

The authors also discovered that circadian rhythm regulation is missing in glioblastoma cells, according to the study.

“We tested to see if inhibition of this cancer-promoting protein in glioblastoma cells would alter their invasive properties,” said co-corresponding author Deborah Bell-Pedersen, PhD. “Indeed, we found that inhibition of p38 MAPK at specific times of the day—times when the activity is low in normal glial cells under control of the circadian clock—significantly reduced glioblastoma cell invasiveness to the level of noninvasive glioma cells.”

These findings suggest that chronochemotherapy may be effective for patients with glioblastoma. This method consists of administering chemotherapy at certain times during the day that have the most significant impact on cancer cell death, according to the study.

“Chronotherapeutic strategies have had a significant positive impact on the treatment of many types of cancer by optimizing the specific timing of drug administration to improve the efficacy and reduce the toxicity of chemotherapy,” Dr Bell-Pedersen said. “However, circadian biology has not been applied to the development of chronotherapeutic strategies for the treatment of glioblastoma, and clinical outcomes for this common primary brain tumor have shown limited improvement over the past 30 years.”

Patients with glioblastoma typically have poor prognoses due to the high risk of recurrence. Current treatments include chemotherapy, surgery, immunotherapy, and radiation, but typically do not prolong life beyond 18 months, according to the study.

“A big reason for poor prognosis for patients with this aggressive type of tumor is that the glioblastoma cells rapidly and unabatedly invade and disrupt the surrounding brain cells,” said researcher Gerard Toussaint, MD.

The authors found that a p38 MAPK inhibitor may reduce the aggressive behavior of glioblastoma cells.

“We found that an inhibitor of p38 MAPK activity would make the cells behave less invasively, and if you can control the invasive properties, you can improve prognosis,” Dr Earnest said.

The study findings also suggest that administering the treatment at certain times of day may be able to boost efficacy and reduce toxicity, according to the authors.

Lowering toxicity is crucial because treatment with a p38 MAPK inhibitor was observed to elicit too many harmful adverse events, according to the study.

“If treatment with the drug can be timed to when the normal glial cells naturally have low activity of p38 MAPK, the addition of the drug might not be as toxic for these cells, and yet would still be very effective on the cancerous cells,” Dr Earnest said.

Due to the positive findings in cell models, the authors plan to analyze the efficacy of p38 inhibitor chronochemotherapy in animal models of glioblastoma.

“We work on a model system, and the reason to do that is that we can make progress quickly, and we always hope that what we’re working on will lead to something useful, and I think this is a prime example of how putting effort into basic research can pay off,” Dr Bell-Pedersen concluded. “We’re very hopeful and encouraged by our data that we’ll find a treatment.”