For the first time, scientists have detailed how a deadly brain cancer has a unique path of progression, aggressively eating away at the skull itself – and how drugs to impede this end up making it worse.
Researchers at Albert Einstein College of Medicine and Montefiore Einstein Comprehensive Cancer Center (MECCC) made their discovery looking at two different types of glioblastomas in mice. Further investigation of human brain scans found that skull thickness had been altered by the tumors, particularly where bones fuse.
“Our discovery that this notoriously hard-to-treat brain cancer interacts with the body’s immune system may help explain why current therapies – all of them dealing with glioblastoma as a local disease – have failed, and it will hopefully lead to better treatment strategies,” said corresponding author Jinan Behnan, an assistant professor at Albert Einstein College of Medicine.
Glioblastoma, the most common type of brain cancer, is particularly aggressive, with less than 7% of patients living beyond five years after diagnosis. In adults, the median survival rate is just 14.6 months.
The researchers found that, in the mice, the erosion of the skull increased the number and size of skull-to-bone channels present, which they believed could be allowing tumor cells to impact marrow, affecting the body’s immune system. Through single-cell RNA sequencing, the team indeed saw that glioblastoma upended the skull bone marrow’s environment – filling it with pro-inflammatory neutrophils while decimating cancer-fighting antibody-producing B cells.
“The skull-to-brain channels allow an influx of these numerous pro-inflammatory cells from the skull marrow to the tumor, rendering the glioblastoma increasingly aggressive and, all too often, untreatable,” said study co-author E. Richard Stanley, professor of developmental and molecular biology at Albert Einstein College of Medicine. “This indicates the need for treatments that restore the normal balance of immune cells in the skull marrow of people with glioblastoma. One strategy would be suppressing the production of pro-inflammatory neutrophils and monocytes while at the same time restoring the production of T and B cells.”
Until now, treatment has generally considered glioblastoma a localized cancer, rather than a systemic disease. Further evidence that suggests it’s not local is that it affects genes in the skull marrow differently to those in femur marrow, suppressing some that boosted inflammatory cells and suppressing others that muted their ability to make immune cells.
The researchers then administered the anti-osteoporosis drugs zoledronic acid and denosumab to the mice, to see if they would also prevent skull-bone loss as well as affect the glioblastoma. Both stopped bone loss, but zoledronic acid also accelerated growth in one type of tumor. And both blocked the positive effects of the immunotherapy drug anti-PD-L1, which ordinarily boosts the production and activity of tumor-fighting T cells.
While early days, the discovery advances our knowledge on just why current treatments for glioblastoma have a low success rate and opens the door to new non-localized approaches in tackling this deadly brain cancer.
The study was published in the journal Nature Neuroscience.
