Tapping circadian rhythm in the fight against glioblastoma

Chronochemotherapy—treating cancer at specific times of the day for the most benefit—may become a viable option for patients with glioblastoma, and lead to more effective treatments that minimize damage to healthy, surrounding tissue, according to results from a study published in BMC Cancer.

“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,” said co-corresponding author Deborah Bell-Pedersen, PhD, biologist at the Center for Biological Clocks Research (CBCR), Texas A&M University, College Station, TX.

“However,” she added, “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.”

Senator John McCain’s diagnosis of glioblastoma earlier this year has put a spotlight on this disease. Harnessing the body’s circadian rhythms may provide novel therapies and approaches for glioblastoma, the most common brain cancer in adults and one that carries a particularly poor prognosis.

Current treatments—including chemotherapy, surgical resection, immunotherapy and radiation—are largely ineffective in prolonging life expectancy beyond 18 months in these patients.

“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 co-author and glioblastoma specialist, Gerard Toussaint, MD, clinician and assistant professor, Texas A&M College of Medicine.

CBCR researchers have found that in glioblastoma, the production of p38 mitogen activated protein kinase (MAPK) is disrupted. MAPK, a signaling molecule that has a key role in the highly invasive and aggressive characteristics of glioblastoma, is associated with tumor growth and proliferation.

In previous work, Dr. Bell-Pedersen, used a model fungal system (Neurospora crassa) to show that the biologic clock controls the daily rhythms of MAPK activity.

In this current study, David J. Earnest, PhD, mammalian biologic clock expert, Texas A&M College of Medicine, and co-corresponding author, worked with Dr. Bell-Pedersen to show that the circadian clock controls daily rhythm in the activity of p38 MAPK in several mammalian cells, including normal glial cells.

This regulation, they found, is absent in glioblastoma cells. So they experimented to see if they could use the body’s circadian rhythm against these cells to suppress them.

“We tested to see if inhibition of this cancer-promoting protein in glioblastoma cells would alter their invasive properties,” said Dr. Bell-Pedersen. “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.”

Added Dr. Earnest, “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.”

Further, p38 MAPK inhibition may not only be more effective, but less toxic if administered at the appropriate time of the day.

“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,” said Dr. Earnest.

Preclinical animal model testing is the next step for the team.

“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. We’re very hopeful and encouraged by our data that we’ll find a treatment,” concluded Dr. Bell-Pedersen.

The research was initiated by Charles S. Goldsmith, first author on the study and a previous graduate student in the Interdisciplinary Genetics Program, who completed his dissertation research in Dr. Bell-Pedersen’s CBCR-affiliated laboratory.