Scientists discover the hidden weakness of a deadly brain cancer

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UC San Francisco scientists have discovered that neural activity in these deadly tumors can restructure connections in surrounding brain tissue, causing the cognitive decline associated with the disease, and that the drug gabapentin, commonly used to prevent seizures , could block this growth-causing activity. in mice with glioblastoma.

The findings, which appear in Naturethey provide a hopeful new direction for research into a disease that has challenged even the most modern and sophisticated types of cancer drugs.

“Glioblastoma needs a win,” said neurosurgeon Shawn Hervey-Jumper, MD, who led the study along with postdoctoral researcher Saritha Krishna, PhD. “This study opens the door to a whole world of treatment possibilities for these patients and a new way of thinking about brain cancer.”

When Hervey-Jumper was beginning her study, scientists had recently discovered that brain tumors are fueled by a positive feedback loop. It begins when cancer cells produce substances that can act as neurotransmitters. This “extra” supply of neurotransmitters stimulates neurons to become hyperactive, which in turn stimulates the growth of cancer cells.

Building on previous studies in mice and brain organoids (small bundles of neurons derived from human stem cells grown in petri dishes), Hervey-Jumper focused on what the feedback loop meant for human behavior and cognition in brain cancer.

The team recruited volunteers awaiting surgery for glioblastoma whose tumors had infiltrated the region of the brain that controls speech. Just before operating on the tumor, Hervey-Jumper placed a grid of tiny electrodes on the surface of the speech region, showed the volunteers images, and asked them to name what they saw.

The research team then compared the results with normal-appearing non-tumor regions of the brain from the same participants. They found that the participants’ tumor-infiltrated brain regions used a larger area-brain neural network in an effort to identify what they were seeing.

Cancer as a conversation between cells

Hervey-Jumper attributes this to the degradation of information processing power in that region of the brain. He likens it to an orchestra where it’s the musicians playing in sync that make the music work.

“If you lose the cellos and woodwinds, the remaining musicians just can’t carry the piece the way they otherwise would,” he said. The brain cells trapped in the tumor are so damaged that others farther away must be recruited to perform the tasks that used to control a smaller area.

The study shows that it is this interaction between cells that causes the cognitive decline associated with brain cancer, rather than inflammation and pressure from tumor growth, as the scientists had thought.

“A brain tumor is not just sitting there dying,” Hervey-Jumper said. “It’s being regulated by the nervous system. It’s having conversations with the cells around it and actively integrating itself into brain circuitry, reshaping the way they behave.”

We haven’t thought about cancer this way

Now, the researchers knew that the tumors were taking advantage of networks in the brain. So they turned to gabapentin, which controls seizures by controlling excess electrical activity in the brain, testing it in mice grafted with human glioblastoma cells.

“The gabapentin actually stopped the tumor from spreading,” Krishna said. “This gives us hope that combining gabapentin with other therapies for glioblastoma could prevent some of the cognitive decline we see in patients and perhaps prolong their lives.”

The findings are likely to translate to other neural cancers, such as those of the spine, and may help explain why the brain is the first site of metastasis for many cancers.

Hervey-Jumper said the study encourages cancer specialists to consider communication networks between cells, such as the positive feedback loop in glioblastoma, as potential targets for treatments, along with genetic and immunological approaches.

“We haven’t thought about cancer this way before,” he said. “The idea that there is a conversation going on between cancer cells and healthy brain cells is something of a paradigm shift.”

Money: This study was supported by National Institutes of Health (grants K08NS110919, P50CA097257, F30CA246808, T32GM007618, K99CA25200, R01NS100440, R00DC013828, R01NS092597, DP1NS111132, and K08CA21227 9; Robert Wood Johnson Foundation (grant 74259); and the American Brain Tumor Association ( grant MSSF1900021).