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Internal Biological Clock Might be Influencing Effectiveness of Glioblastoma Therapy

The circadian clock is the basis for biological time keeping in eukaryotic organisms. The clock mechanism relies on biochemical signaling pathways to detect environmental stimuli and to regulate the expression of clock-controlled genes throughout the body.

Your circadian rhythm is a natural, internal system that’s designed to regulate feelings of sleepiness and wakefulness over a 24-hour period. This complex timekeeper is controlled by an area of the brain that responds to lights, which is why humans are most alert while the sun is shining and are ready to sleep when it’s dark outside.

Scientists at the Texas A&M University’s Center for Biological Clocks Research have now found evidence linking Circadian rhythms and novel therapies for glioblastoma.

MAPK signaling pathways function in both circadian input and output pathways in mammals depending on the tissue; however, little is known about the role of p38 MAPK, an established tumor suppressor, in the mammalian circadian system.

The new study shows that the clock controls daily rhythms in p38 MAPK activity in a variety of mammalian cells as well, including normal glial cells, the supporting “helper” cells surrounding neurons. Furthermore, their work found that such regulation is absent in glioblastoma cells.

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Internal Biological Clock Might be Influencing Effectiveness of Glioblastoma Therapy
Neurospora crassa samples growing in Bell-Pedersen’s Center for Biological Clocks Research laboratory. The bands in the tubes indicate the daily rhythm of spore formation in the fungus.

This work is based on a previous one carried out by Texas A&M biologist Deborah Bell-Pedersen, Ph.D., a co-corresponding author on the study, who found that the biological clock in the model fungal system Neurospora crassa controls daily rhythms in the activity of a signaling molecule called p38 mitogen activated protein kinase (MAPK).

We tested to see if inhibition of this cancer-promoting protein in glioblastoma cells would alter their invasive properties,” said Bell-Pedersen, an internationally recognized leader in the fields of circadian and fungal biology. “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 indicate that glioblastoma might be a good candidate for chronochemotherapy — treating cancer at specific times of day to get the most impact.

Internal Biological Clock Might be Influencing Effectiveness of Glioblastoma Therapy
A member of the Texas A&M Biology faculty since 1997, Deborah Bell-Pedersen is an internationally recognized leader in the fields of circadian and fungal biology. In addition to helping to sequence the genome for Neurospora crassa (bread mold), her laboratory made the first DNA chips containing the fungus’s genes, which led to major insights into its biological clock.

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,” 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.

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Through detailed a investigation, the team was able to find 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. In addition, the team’s data indicate such treatment may be more effective and less toxic if administered at the appropriate time of the day. This reduced toxicity is important, because a drug to inhibit the cancer-promoting activity of this protein was tested but found to be too harmful, with too many side effects.

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,” Earnest said.

The team’s next step is to test p38 inhibitor chronochemotherapy in an animal model for glioblastoma. If successful, they would then move on to clinical trials.

We work on a model system, and the reason to do that is that we can make progress quickly,” Bell-Pedersen said. “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.

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