Glioblastoma multiforme is an aggressive brain tumor that mainly affects adults. Approximately 30,000 people in the U.S. are diagnosed with GBM every year and patients have a 5-year survival rate of 7%. Current treatments include surgery, radiation therapy and chemotherapy with temozolomide. Unfortunately, none of these methods can cure GBM.
In a study appearing in Small, University of Michigan researchers have created nanodiscs that can target cholesterol levels in GBM, starving the cancer cells and increasing survival rates of the treated mice.
“Treatment options for GBM have their limitations,” said Maria Castro, professor of neurosurgery and a member of the Rogel Cancer Center.
“Although surgery can help improve survival, surgeons often have to remove the normal tissue that surrounds the tumor to prevent it from spreading. On the other hand, using drugs to target the cancer is also challenging because GBM cells are heterogeneous. If you try and target a particular pathway, the cancer cells can use other pathways and repopulate the tumor.”
Additionally, anti-cancer drugs cannot easily cross the blood-brain barrier, which protects the brain from substances in the blood, according to Anna Schwendeman, professor of pharmaceutical sciences.
Nanodiscs reduce cholesterol levels in GBM cells
Previous studies have shown that GBM tumors require cholesterol to proliferate. However, they are unable to make enough of it and instead import cholesterol from other cells.
The team created specific nanodiscs and injected them into mouse models for GBM.
“Our goal was to provide surgeons with the option to inject these particles into the tumor cavity after they have removed the tumor mass,” said Troy Halseth, former graduate student at Schwendeman and co-first author on the study.
“It is important to focus on local delivery because chemotherapy drugs are toxic and can cause several side effects.”
The nanodiscs were synthesized to deliver Liver-X-Receptor agonists to the cancer cells. These molecules increase the number of pumps that can export cholesterol out of the tumor cells, resulting in their death.
When used in combination with radiation therapy, more than 60% of the mice survived when compared to the mice that only received radiation.
“We included radiation because it is the standard procedure of care for GBM patients. Therefore, any new therapy must be given in addition to radiation,” said Anzar Mujeeb, postdoctoral fellow in the Castro lab and co-first author on the study.
The combined treatment was able to preserve normal brain structure and there were no adverse side effects.
Nanodiscs boost the immune response against GBM tumors
The nanoparticles also had CpG oligonucleotides on their surface, which activate the body’s immune system. As a result, immune cells not only attack the tumor, but also retain the memory and are able to attack any future tumors.
“The main cause of death in glioma patients is not the primary cancer, which is usually removed efficiently by surgeons. Instead, it is when the tumor comes back,” Castro said. “We wanted to address that problem as well.”
The researchers discovered that in addition to prolonging the survival rates, the nanodiscs also elicited an immunological memory and 68% of the surviving mice eliminated the second tumor that was introduced into their bodies.
The team is now working on scaling up the synthesis of these particles and planning a clinical trial.
“This study would not have been possible without the interdisciplinary collaboration between U-M cancer biologists and drug delivery experts from the School of Pharmacy,” Schwendeman said.
