Franziska Michor, PhD
The study, published online by the journal Cell, involves glioblastoma, a brain malignancy diagnosed in almost 3,000 people each year in the United States. Because the research involved mice, the study does not recommend a specific new schedule for human patients, but the findings demonstrate that modifying the standard administration schedule of radiotherapy can make the treatment more effective, the authors say.
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.
“There have been many attempts over the years to develop a more effective radiation therapy schedule for patients with this disease, but none has proven superior to the standard approach, which has now been in use, essentially unchanged, for more than 50 years,” says Franziska Michor, PhD, principal investigator of the Physical Science – Oncology Center at Dana-Farber, who is co-senior author of the study with Eric Holland, MD, PhD, of the Fred Hutchinson Cancer Research Center. “An array of recent advances in the understanding of the basic biology of glioblastoma led us to try a fresh approach to the problem.”
Glioblastoma is a malignant 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 can. 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 says. “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 and her colleagues focused on a subtype of glioblastoma with an abnormal cell-signaling pathway that involves abnormal signaling 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.
“In radiotherapy, timing is everything,” Michor relates. “Irradiating too frequently would increase side effects and toxicity. Irradiating too infrequently would give the tumor cells too much opportunity to grow.”
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 similar mice treated under the standard schedule. The improvement was attention-getting: 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 state, but studies are under way that more closely replicate the conditions of human treatment.
“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 remarks. “The fact that we’ve accomplished this in animals raises the hope that we can achieve similar results in humans.”
The co-lead authors of the study are Kevin Leder, PhD, of the University Minnesota and Ken Pitter of Memorial Sloan-Kettering Cancer Center. Co-authors are Quincey LaPlant, PhD, and Timothy Chan, MD, PhD, of Sloan-Kettering, Dolores Hambardzumyan, PhD of the Cleveland Clinic; and Brian Ross, PhD, of the University of Michigan.
Funding for the study was provided by grants RO1 CA100688, U54 CA163167, U54 CA143798, U01 CA141502-01, U54 CA143798, NSF DMS-1224362, U54 CA143798, MSTP GM07739, F31 NS076028, and P01 CA085878 from the National Institutes of Health.
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