Researchers eye altered radiation schedule as way to improve brain cancer treatment

Fred Hutch’s Dr. Eric Holland collaborates with Dana-Farber on promising mouse study

An altered radiation treatment schedule for the most common and lethal form of brain cancer has been shown to extend the survival period of mice with the disease, which suggests that some alteration in schedule may be able to do the same for human patients.

These findings, published online Jan. 30 in the journal Cell, involves glioblastoma, a brain malignancy diagnosed in 17,000 people each year in the United States. Because the research involved mice, the findings do not indicate a specific new radiation treatment schedule for human patients, but they demonstrate that modifying the standard administration schedule of radiotherapy can make the treatment more effective.

The study was a joint effort between a team of computational biologists at the Dana- Farber Cancer Institute in Boston lead by Dr. Franzisca Michor and the laboratory of Dr. Eric Holland, director of the Human Biology Division at Fred Hutchinson Cancer Research Center, the Alvord Brain Tumor Center at the University of Washington, and Solid Tumor Translational Research across both institutions. Michor and Holland are also principal and co-principal investigators of the Physical Sciences-Oncology Center at Dana-Farber.

The research is based on a new understanding of how glioblastoma cells respond to radiation therapy, and how that response toughens them against the ravages of radiation.

“Radiation is the most effective post-surgical treatment for glioblastoma. Although there have been many attempts over the years to develop a more effective radiation therapy schedule for patients with this disease, none have proven superior to the standard approach, which has now been in use, essentially unchanged, for more than 50 years,” Holland said.

“An array of recent advances in the understanding of the basic biology of glioblastoma led us to try a fresh approach to the problem,” Michor said.

Glioblastoma is a brain cancer that is more common in older people than in young and affects more men than women. Treatment generally consists of surgery, chemotherapy and radiation therapy. While the clinical management of the disease can extend patients’ lives, it is currently incurable; the median survival of treated patients is about 15 months.

The new study was spurred by advances in three areas: the discovery of different subtypes of glioblastoma based on the abnormal genes within their cells; the development of better mouse models of the disease in humans; and the discovery that some of the cells in glioblastoma tumors are similar to stem cells – immature cells that can withstand radiation therapy better than most glioblastoma cells.

Recently, scientists discovered that radiation therapy can cause glioblastoma cells to “de-mature” – to revert to a state where they’re more like stem cells and more resistant to being killed by radiation.

“There’s a dynamic equilibrium within glioblastoma tumors in which cells are shifting between an immature and mature state,” Michor said. “We set out to see if we could use our understanding of this process to enhance the effectiveness of radiotherapy.”

For the current study, Michor, Holland and colleagues focused on a subtype of glioblastoma with an abnormal cell-signaling pathway induced by the protein PDGF (platelet-derived growth factor). Such tumors account for about 30 percent of all glioblastomas.

The research team developed a mathematical model of the effect of radiation on glioblastoma cells – how quickly it prompts the cells to become more stem-like, how likely it is to kill cells, and how long these and other processes take. They then used the formulas to devise a treatment schedule that would, in theory, prolong survival.

The standard radiotherapy schedule for patients with glioblastoma is 2 Grays (or Gy, a standard unit of absorbed radiation) per day, five days a week, for six weeks. The researchers identified a schedule for delivering a total of 10 Gy that was predicted to produce better results in mice. This optimum schedule administers the same total amount of Gy, but in a different temporal order.

They tested the new schedule in mice with glioblastoma and found that, indeed, they survived longer than mice treated with the standard schedule. The improvement was significant: Mice treated under the standard schedule survived a median period of 33 days, compared to 50 days for the mice treated under the new schedule.

Because human glioblastoma patients usually receive a chemotherapy drug in conjunction with radiotherapy, and because the time scales of treatment response might be different from those in mice, the new schedule might not have an equally beneficial effect in patients, the authors stated, but studies are under way that more closely replicate the conditions of human treatment.

“This study strongly suggests that tumors respond to standard therapies in a dynamic way such that cells unexpectedly acquire resistance in a rapid time scale,” Holland said. “The results in mice will hopefully help us identify the right sequence of therapy in people. It is possible that the current schedule is not optimal.”

“Our model demonstrates that a revised dosing schedule can increase the number of stem-like cells in glioblastoma tumors, and still slow the overall growth of the tumor and delay the time until tumor growth recurs,” Michor said. “The fact that we’ve accomplished this in animals raises the hope that we can achieve similar results in humans.”

The study, funded by the National Institutes of Health and the National Science Foundation, also involved researchers from the University Minnesota, Memorial Sloan-Kettering Cancer Center, Cleveland Clinic and the University of Michigan.

Adapted from a Dana-Farber Cancer Institute news release. 

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