Researchers from Sanford Burnham Prebys have collaborated the University of Pittsburgh Cancer Institute to reveal a new approach to enhance the effects of immunotherapy in glioblastoma, one of the most aggressive and treatment-resistant forms of brain cancer.

The study, published recently in Cancer Discovery, describes a novel method to ‘turn off’ cancer stem cells—the malignant cells that self-renew and sustain tumors—enabling the body’s own defense system to take charge and destroy tumors.

“Tumors are more than just masses of cells—each one is a complex system that relies on a vast network of chemical signals, proteins and different cell types to grow,” says senior author Charles Spruck, PhD, an assistant professor at Sanford Burnham Prebys. “This is part of why cancer is so difficult to treat, but it also presents us with opportunities to develop treatment strategies that target the machinery powering tumor cells rather than trying to destroy them outright.”

Glioblastoma is an extremely aggressive form of cancer that affects the brain and the spinal cord. Occurring more often in older adults and forming about half of all malignant brain tumors, glioblastoma causes worsening headaches, seizures and nausea. And unfortunately for the thousands of people who receive this diagnosis each year, glioblastoma is most often fatal.

“We haven’t been able to cure glioblastoma with existing treatment methods because it’s just too aggressive,” says Spruck. “Most therapies are palliative, more about reducing suffering than destroying the cancer. This is something we hope our work will change.”

Immune checkpoint inhibitors—which help prevent cancer cells from hiding from the immune system—can be effective for certain forms of cancer in the brain, but their results in glioblastoma have been disappointing. The researchers sought a way to improve the effects of these medications.

“Modern cancer treatment rarely relies on just one strategy at a time,” says Spruck. “Sometimes you have to mix and match, using treatments to complement one another.”

The researchers used genomic sequencing to investigate glioblastoma stem cells. These cells are the source of the rapid and consistent regeneration of glioblastoma tumors that make them so difficult to treat.

The team successfully identified a protein complex called YY1-CDK9 as essential to the cells’ ability to express genes and produce proteins. By modifying the activity of this protein complex in the lab, the team was able to improve the effectiveness of immune checkpoint inhibitors in these cells. 

“Knocking out this transcription machinery makes it much more difficult for the cells to multiply” says Spruck. “They start to respond to chemical signals from the immune system that they would otherwise evade, giving immunotherapy a chance to take effect.” 

While the approach will need to be tested in clinical settings, the researchers are optimistic that it may provide a way to improve treatment outcomes for people with glioblastoma. 

“What our results tell us is that these cells are targetable by drugs we already have, so for patients, improving their treatment may just be a matter of adding another medication,” adds Spruck. “For a cancer as treatment-resistant as glioblastoma, this is a great step forward.”