Glioblastoma multiforme (GBM) is a highly aggressive brain cancer that primarily affects adults. Every year, approximately 30,000 people in the U.S. are diagnosed with GBM, and the five-year survival rate for patients is only 7%.

The current treatment options for GBM include surgery, radiation therapy, and chemotherapy with temozolomide. However, none of these methods are curative.

In a recent study, researchers from the University of Michigan developed nanodiscs that target cholesterol levels in GBM cells, effectively starving the cancer and improving survival rates in treated mice.

“Treatment options for GBM have their limitations,” said Maria Castro, a professor of neurosurgery and a member of the Rogel Cancer Center. “While surgery can improve survival, it often involves removing surrounding healthy tissue to prevent the tumor from spreading. Additionally, targeting cancer cells with drugs is difficult because of the tumor's heterogeneous nature, and the cells can often bypass targeted treatments by using other pathways.”

Another challenge is the blood-brain barrier, which prevents many anti-cancer drugs from reaching the brain, as explained by Anna Schwendeman, a professor of pharmaceutical sciences.

The researchers discovered that GBM tumors rely on cholesterol for growth but are unable to produce enough on their own, instead importing it from surrounding cells. To exploit this vulnerability, the team designed specialized nanodiscs and injected them into mouse models with GBM.

“Our goal was to give surgeons the option to inject these particles into the tumor cavity after removing the tumor mass,” said Troy Halseth, former graduate student in Schwendeman's lab and co-first author of the study. “Local delivery is key because chemotherapy drugs are toxic and can cause severe side effects.”

The nanodiscs were designed to deliver Liver-X-Receptor (LXR) agonists, which increase the activity of pumps that expel cholesterol from the tumor cells. This depletion of cholesterol leads to tumor cell death.

“The main cause of death in glioma patients isn’t usually the primary cancer, which can be effectively removed by surgeons, but rather the recurrence of the tumor,” said Maria Castro. “We aimed to address this issue as well.”

When combined with radiation therapy, the treatment resulted in more than 60% of the mice surviving compared to those who only received radiation. "We included radiation because it's the standard care for GBM patients, so any new therapy must be administered alongside it," said Anzar Mujeeb, postdoctoral fellow in the Castro lab and co-first author of the study.

This combination therapy also preserved normal brain structure, with no adverse side effects observed.

The nanodiscs also contained CpG oligonucleotides on their surface, which activate the immune system. This not only prompted immune cells to attack the tumor but also generated immunological memory, allowing the immune system to combat any future tumors.

“The main cause of death in glioma patients is tumor recurrence, not the primary cancer,” Castro added. “We wanted to address this issue as well.”

The researchers found that, in addition to improving survival rates, the nanodiscs triggered immune memory, with 68% of the surviving mice rejecting a second tumor introduced later.

The team is now focused on scaling up the production of these nanodiscs and preparing for clinical trials.

“This study wouldn’t have been possible without the interdisciplinary collaboration between U-M cancer biologists and drug delivery experts from the School of Pharmacy,” said Schwendeman.

Source: https://www.newswise.com/articles/researchers-use-nanoparticles-to-target-glioblastoma-in-mice