Chemotherapy for glioblastoma improved by exploiting circadian rhythms of cells

Glioblastoma is an aggressive form of brain cancer for which there is no cure. A recent study of glioblastoma patients found that taking chemotherapy in the morning was associated with a three to six month increase in median survival.

Now, research from Washington University in St. Louis reports that glioblastoma cells have built-in circadian rhythms that create more favorable timing for treatment.

Biologists and clinicians have documented circadian rhythms in the expression of “clock genes” from various cultured human and mouse glioblastoma cell lines and isolates. These rhythms coincided with the daily activity of a DNA repair enzyme known as MGMT.

The scientists then ran tests and found that tumor cells were more likely to die when chemotherapy was given at a time of day—in the morning—when the tumor cells had the least MGMT activity.

Replicating their efforts in mice with glioblastoma, the scientists found that morning administration of chemotherapy reduced tumor size and increased body weight compared with evening administration of the drug.

"It may be possible to better treat this disease with medication at times of day when cells are more receptive," said Maria F. Gonzalez-Aponte, a biology graduate student in the University of Washington College of Arts and Sciences who is the first author of the new study..

"We found that administering chemotherapy with temozolomide (TMZ) in the subjective morning can significantly reduce tumor growth and improve treatment outcomes for human and mouse models of glioblastoma."

"Because TMZ is taken orally at home, translating these results to patients is relatively simple," said Eric D. Herzog, Ph.D., Victor Hamburger Distinguished Professor and Professor of Biology in the College of Arts and Sciences, corresponding author of the new study.

"We will need additional clinical trials to confirm our laboratory findings, but current evidence suggests that standard treatment for glioblastoma can be improved simply by asking patients to take an approved drug in the morning," Herzog said.

Although the practice of taking time of day into account in disease management has been little studied for TMZ and glioblastoma, the study authors noted that it has been shown to improve outcomes in several types of cancer, including acute lymphoblastic leukemia, colorectal and ovarian cancer, and other gynecological cancers. p>

Joshua B. Rubin, M.D., Ph.D., professor of pediatrics and neuroscience at the medical school, a longtime collaborator in Herzog's laboratory, and co-author of the paper. Gary J. Patty, Ph.D., professor of chemistry in the College of Arts and Sciences and Medicine in the medical school, and research assistant Kevin Cho, Ph.D., in chemistry are also co-authors.

The findings of this study have implications for both the treatment and diagnosis of glioblastoma.

In general, glioblastoma patients diagnosed with so-called MGMT methylated tumors tend to respond better to chemotherapy with TMZ.

But this study showed that MGMT methylation levels rise and fall depending on the circadian time of the tumor. As a result, doctors must consider the time of day when a tumor biopsy is taken to properly compare results and improve diagnosis, the study authors noted.

"Despite extensive research over the past 20 years, the median survival of patients with glioblastoma after treatment remains at about 15 months, which is a grim statistic," Herzog said. "Introducing chronic therapy, or timely administration of medications, can help improve the situation."

The study is published in theJournal of Neuro-Oncology.