Aggressive Brain Cancer Progression Blocked by Protein Inhibition

Blocking access to a signaling molecule created by nerve cells may stop the growth of aggressive brain cancers, according to a new study published by Nature.

High-grade gliomas are known to be particularly aggressive and include adult glioblastoma, anaplastic oligodendroglioma, pediatric glioblastoma, and diffuse intrinsic pontine glioma (DIPG), which affects children. The 5-year survival rates are approximately 10% for glioblastoma and much lower for DIPG, highlighting the urgent need for novel therapies.

In mice, the absence or interruption of the signaling molecule neuroligin-3 was found to stop the spread of high-grade gliomas, suggesting its role in cancer proliferation.

"We thought that when we put glioma cells into a mouse brain that was neuroligin-3 deficient, that might decrease tumor growth to some measurable extent. What we found was really startling to us: For several months, these brain tumors simply didn't grow," said Michelle Monje, MD, PhD.

The authors hypothesize that modifying the neuroligin-3 signal may be an effective strategy for controlling high-grade gliomas in humans, according to the study.

Previously, the authors found that neuroligin-3 contributed to the growth of brain cancers. These findings were surprising since the protein is involved with neuroplasticity of the healthy brain and it was not previously known that the cancer could take over healthy functions to increase disease proliferation, according to the authors.

Included in the new study were neuroligin-3 knock out mice who had normal brain function. When human high-grade glioma cells were implanted, cancer cells did not proliferate. This lack of cell growth was observed to last for several months, according to the study.

"Lack of neuroligin-3 doesn't kill the cancer cells; the cells that are there remain there, but they do not grow," Dr Monje said.

After 4.5 months, some tumors bypassed dependence on the signaling protein and started to grow again, according to the study.

The authors also implanted human breast cancer cells in the brains of knockout mice. The breast cancer cells continued to grow, suggesting that dependence on neuroligin-3 may be specific to high-grade gliomas.

These effects were found across various forms of high-grade gliomas. Due to these findings, the authors examined the cell signals involved with neuroglin-3’s role in glioma cell division.

The authors discovered that neuroligin-3 activates cancer-promoting pathways and ramps up the expression of genes involved with proliferation, malignancy, function of potassium channels, and synapse function, according to the study.

Although more research is needed, the authors hypothesize that neuroligin-3 does more than prevent glioma cell division.

The investigators also examined whether blocking the protein may be a promising treatment for gliomas. They tested 2 inhibitors of neuroligin-3 in mice with normal signaling and high-grade glioma.

The authors found that both inhibitors reduced glioma growth, suggesting it could be effective in humans. One of the drugs has reached phase 2 clinical trials as a chemotherapy for non-brain cancers, according to the study.

"We have a really clear path forward for therapy; we are in the process of working with the company that owns the clinically characterized compound in an effort to bring it to a clinical trial for brain tumor patients," Dr Monje said.

However, the authors note that inhibiting neuroligin-3 will not cure high-grade gliomas, as it does not kill cancer cells, but it shows promise as a combination therapy.

"We will have to attack these tumors from many different angles to cure them," Dr Monje said. But given how devastating the tumors are, the possibility of using neuroligin-3 inhibition to slow tumor progression is a hopeful development, she added. "Any measurable extension of life and improvement of quality of life is a real win for these patients."