June 29, 2016
Researchers at the University of North Carolina at Chapel Hill seeking a better treatment for glioblastoma have discovered that removing a brain tumor causes any cancer left behind to grow 75 percent faster than the original tumor did, which helps to explain why this cancer is so lethal.
“The thing that is deadly about this disease is that it diffusely invades the brain. Unlike tumors elsewhere in the body, you can’t cut it all out,” said Ryan Miller, M.D., Ph.D., a neuropathologist and an associate professor at the UNC School of Medicine and member of the UNC Lineberger Comprehensive Cancer Center.
Glioblastoma is a highly aggressive form of brain cancer and accounts for approximately one in six brain tumors. It is typically treated with a combination of surgery, radiation and chemotherapy, though treatments are tailored for each patient based on the tumor’s size and location.
Researchers led by Shawn Hingtgen, Ph.D., an assistant professor in the UNC Eshelman School of Pharmacy and a UNC Lineberger member, are working to perfect a stem-cell treatment that can hunt down and kill the cancer cells that are inevitably left behind when a brain tumor is surgically removed. To properly test their treatment, they had to develop a mouse model of the brain after surgery.
“A key part of developing our stem-cell therapies and advancing them toward use in patients is testing them in models that look like what’s going to happen in a patient,” Hingtgen said. “Testing them in a model that contains a solid tumor is not accurate in many ways.”
Developing the new model fell to Onyi Okolie, a graduate student working in Hingtgen’s laboratory in the UNC Eshelman School of Pharmacy. Unlike mice typically used to test drugs, this new model has a full immune system. A tumor is implanted and allowed to grow to the point where a patient would start experiencing symptoms, such as headache, seizures or an altered mental state. Okolie then removes about 90 percent of the tumor, which is comparable to what surgeons are able to remove in human patients.
“Surgery is the mainstay of therapy for glioblastoma, but not much is known about what happens after we operate,” Miller said. “We develop all of our postoperative treatments based on research using well-established tumors, but we don’t know what the process of removing the tumor does to the cancer.”
The trauma of surgery causes astrocytes, which are star-shaped glial cells that support and maintain the brain and neurons, to secrete chemicals that announce the injury. The team now knows that these signals reach the cancer cells and spur them into action.
“The remaining cancer cells multiply and they move, both of which are not good,” Hingtgen said. “We were able to extend survival as we expected, but we saw that the regrowth rate was significantly increased compared to the growth rate of the preoperative tumor. The tumor was now more aggressive. We realized that we changed something with the surgery.”
The UNC team saw that the cancer cells began moving and growing approximately 75 percent faster than they did before the tumor was removed. Their findings are published in the journal Neuro-Oncology.
The study also points out a real problem, Miller said. Drugs are developed against large, solid tumors, but they’re actually used to treat the residual disease: the two things are not the same.
“Surgery has to be done, but the disease is fundamentally different before and after surgery,” he said. “Preclinical drug development is being done on a disease model that is fundamentally different from the state of the disease in a patient after surgery. We need to come up with something better.”
The new model will allow researchers to understand the effect of surgery on the brain and the tumor and potentially identify new therapeutic targets to make postoperative care better, Hingtgen said.
“In cancer, we always ask is it the seed or the soil?” Miller said. “A seed can go bad and turn cancerous, or the soil can turn a bad seed worse. Surgery changes the soil and makes the bad seed much more aggressive.”
Authors and Funding
The study was supported by funding from the National Cancer Institute, the University Cancer Research Fund and the UNC Translational and Clinical Sciences Institute. The authors are
- Onyinyechukwu “Onyi” Okolie, a graduate student at the UNC Eshelman School of Pharmacy;
- Juli R. Bago, Ph.D., a postdoctoral research associate at the UNC Eshelman School of Pharmacy;
- Ralf S. Schmid, Ph.D., a research associate at the UNC School of Medicine and a member of UNC Lineberger;
- David M. Irvin, M.S., a graduate student at the UNC School of Medicine;
- Ryan E. Bash, M.S., a research specialist at the UNC School of Medicine;
- Ryan Miller, M.D., Ph.D., an associate professor at the UNC School of Medicine and member of UNC Lineberger and the UNC Neuroscience Center; and
- Shawn D. Hingtgen, Ph.D., an assistant professor in the UNC Eshelman School of Pharmacy and a member of UNC Lineberger and the UNC Biomedical Research Imaging Center.