Common seizure drug blocks deadly brain cancer growth

Summary: Researchers have discovered a promising new avenue for the treatment of glioblastoma, a deadly brain cancer.

The study found that these tumors restructure connections in surrounding brain tissue, leading to cognitive decline. The team found that the drug gabapentin, commonly used to prevent seizures, could inhibit this activity in mice with glioblastoma.

This new study offers a new perspective on brain cancer treatment and could lead to better patient outcomes.

Highlights:

1. Glioblastoma, a notoriously difficult to treat brain cancer, impairs connections in the brain, causing cognitive decline. This newly discovered disease mechanism involves a feedback loop where cancer cells trigger neurons to become overactive, promoting tumor growth.
2. The drug gabapentin, traditionally used for seizure prevention, has been shown to inhibit this hyperactivity, thereby blocking tumor growth in mice with glioblastoma. This suggests a potential new direction for the treatment of glioblastoma.
3. This groundbreaking research indicates that cellular communication networks, such as the positive feedback loop seen in glioblastoma, could be targeted for treatment alongside traditional genetic and immunological approaches, representing a significant paradigm shift in understanding cancer .

Source: UCSF

Glioblastoma, a hard-to-treat brain cancer, steals a person’s mental faculties as it spreads, but the tumor’s insidious ability to infiltrate neighboring networks in the brain could also prove its downfall.

UC San Francisco scientists have found 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-inducing activity. in mice with glioblastoma.

The findings, published in Natureprovide 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 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 his study, scientists had recently discovered that brain tumors are powered by a positive feedback loop. It begins when cancer cells produce substances that can act as neurotransmitters. This “extra” supply of neurotransmitters causes neurons to become overactive, which in turn stimulates the growth of cancer cells.

Building on previous studies done 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 the human behavior and cognition in brain cancer.

The team recruited volunteers awaiting surgery for a glioblastoma whose tumors had infiltrated the region of the brain controlling 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 brain regions from the same participants. They found that the participants’ tumor-infiltrated brain regions used a larger neural network of brain areas 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 this region of the brain. He compares it to an orchestra where the musicians playing in synchrony make the music work.

“If you lose the cellos and the woodwinds, the remaining players just can’t carry the piece the way they otherwise would,” he said. Tumor-related brain cells are so damaged that others must be recruited from further afield to perform tasks that were previously controlled by a smaller area.

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

“A brain tumor isn’t just sitting there dying,” Hervey-Jumper said. “It’s regulated by the nervous system. It is having conversations with the cells around it and actively integrating into brain circuitry, reshaping their behavior.

We didn’t think of cancer that way

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

“Gabapentin actually stopped the tumor from growing,” Krishna said. “This gives us hope that combining gabapentin with other glioblastoma therapies could stave off some of the cognitive decline we’re seeing in patients and possibly extend their lives.”

The findings will likely translate to other neural cancers, such as those of the spine, and could help explain why the brain is the first site of metastasis in 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, as well as genetic and immunological approaches.

“We had never thought of cancer this way before,” he said. “The idea that there’s a conversation between cancer cells and healthy brain cells is kind of a paradigm shift.”

Funding: This study was supported by the National Institutes of Health (grants K08NS110919, P50CA097257, F30CA246808, T32GM007618, K99CA25200, R01NS100440, R00DC013828, R01NS092597, DP1NS111132, and K08CA2122 7 9; Robert Wood Johnson Foundation (grant 74259); and the American Brain Tumor Association (grant MSSF1900021).

About this brain cancer research news

Author: Robin Marks
Source: UCSF
Contact: Robin Marks – UCSF
Picture: Image is credited to Neuroscience News

Original research: Access closed.
“Glioblastoma remodeling of human neural circuitry decreases survival” by Shawn Hervey-Jumper et al. Nature

Abstract

Glioblastoma remodeling of human neural circuitry decreases survival

Gliomas integrate synaptically into neural circuits. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth and gliomas increasing neuronal excitability.

Here, we sought to determine how glioma-induced neural changes influence the neural circuits underlying cognition and whether these interactions influence patient survival.

Using intracranial brain recordings during lexical search tasks in awake humans, as well as site-specific tumor tissue biopsies and cell biology experiments, we find that gliomas remodel the functional neural circuits of so that task-relevant neural responses activate the tumor-infiltrated cortex far beyond the cortical regions. which are normally recruited in the healthy brain.

Site-directed biopsies of regions of the tumor that exhibit high functional connectivity between the tumor and the rest of the brain are enriched for a subpopulation of glioblastoma that exhibits a distinct synaptogenic and neuronotrophic phenotype.

Tumor cells in functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions seen in functionally connected tumor regions compared to tumor regions with less functional connectivity.

Pharmacological inhibition of thrombospondin-1 using gabapentin, an FDA-approved drug, decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively affects both patient survival and performance in language tasks.

These data demonstrate that high-grade gliomas functionally remodel neural circuitry in the human brain, which both promotes tumor progression and impairs cognition.