Researchers at the University of Massachusetts Medical School (UMMS) have identified a novel approach of combining chemotherapy with a targeted therapy to decrease the recurrence of glioblastoma multiforme, the most common and aggressive brain tumor.
“Glioblastomas are horrendous tumors and new therapies are desperately needed,” said Alonzo H. Ross, PhD (pictured), professor of biochemistry and molecular pharmacology at UMMS and lead researcher on the study. “We found that this double therapy of combining temozolomide with a Notch inhibitor was highly effective at treating tumor cells in culture and in mice,” he added.
Despite treatment with surgery, radiotherapy, and chemotherapy, the survival rate for someone with a glioblastoma prognosis is poor. This may be due in part to the fact that some cells within the tumor—cancer stem cells—are more resistant to these therapies, eventually allowing the tumor to recur, according to Ross.
“We’re both very successful and unsuccessful with cancer therapy; in most cases we can substantially diminish the tumor mass. The problem is that it comes back with vengeance, and is even more resistant and difficult to treat,” he said.
Temozolomide is one chemotherapeutic agent that helps patients with glioblastomas live longer; 2-year survival rates increase from approximately 10 percent with radiation alone to 25 percent when temozolomide is combined with radiation, according to Ross. Likewise, data have indicated that the Notch signaling pathway is often over-expressed in glioma tissue and tumor cells.
Ross and colleagues evaluated this double-therapy approach of combining temozolomide with a Notch inhibitor in cell culture and in immunodeficient mice to determine if this combination therapy enhances therapy to reduce tumor recurrence.
In both models, researchers saw that the combination of temozolomide with the Notch inhibitor more effectively reduced tumor growth and recurrence compared to either agent alone. Either drug used individually slowed tumor growth only transiently.
“Temozolomide is a chemotherapy drug of choice for glioblastomas, and the results of our preclinical study represent a potentially promising new approach to combat an extremely difficult tumor,” Ross said. “The effect of the two together is very dramatic.”
Ross and his colleagues worked with Richard P. Moser, MD, UMMS professor of surgery and radiation oncology and chief of neurosurgery at UMass Memorial Medical Center, who has considerable experience in treating glioblastoma patients. “Progress in the treatment of glioblastoma has been very slow over the last 25 years. There has been only a 3.5-month advance in median survival in that time,” he said. Although the double-therapy approach was not the immediate target of the research, he noted, it evolved as a result of collaboration among “bright graduate students, determined professors, a great deal of work, and just a bit of luck. This is the essence of translational research for me,” he said. “Only by working together was it possible to move this very difficult problem from the bedside to the bench and, we soon hope, back to the bedside.”
Patrick M. O’Connor, PhD, chief scientific officer at Selexagen Therapeutics and a member of the editorial board for Cancer Research, believes this study provides preclinical proof-of-concept evidence that the Notch pathway confers a survival advantage to glioma cells treated with temozolomide.
“These results help lay the groundwork for future clinical research and are yet another stepping stone toward a future era dominated by ‘precision therapeutics’ designed to specifically target the underlying molecular drivers of cancer growth and spread,” said Dr. O’Connor.
The researchers are currently investigating the mechanism of action for cell death and hope to move these findings into the clinic.
Illustration: University of Massachusetts Medical School.
University of Massachusetts Medical School News Release (08/25/10)
Abstract (Cancer Research; 70(17), 6870-6879 (09/01/10))