Animal Study Hints That GABA(A) Receptors Could Be Key To Enhancing Treatment of Lung Cancer That Has Spread to the Brain

Nonsmall cell lung cancer (NSCLC) represents approximately 85% of primary lung cancers. Moreover, approximately 40% of lung cancer patients develop brain metastases over the course of the disease, and on average, survive between eight to 10 months following diagnosis.

While radiation therapy is often used to treat NSCLC when spread to the brain, radiotherapy responses have proven not to be durable and toxicity limits therapy.

A new study, led by researchers from the University of Cincinnati, looked to discover a new way for radiation to be more effective and show outcome improvements for patients with lung cancer patients, where the cancer has moved to the brain, hoping to reduce the toxicity.

By using animal models for lung cancer brain metastases, the researchers examined AM-101 and its impact on radiation treatment.

The study, published in Cancers on Sept. 15, 2024, found that AM-101, a benzodiazepine analog, enhances the effects of radiation and significantly improves the survival of mice with lung cancer brain-metastatic tumors.

What’s more, AM-101 improved radiation treatment, slowing down the growth of NSCLC subcutaneous xenograft tumors in mice, by activating the GABA(A) receptor in lung cancer cells, triggering selective autophagy.

In ttheir findings, the researchers noted AM-101’s mode of action showed that it depolarizes the mitochondrial transmembrane potential of cancer cells as well as activating the intrinsic (mitochondrial) apoptotic pathway. So, by activating GABA(A) receptors, it offers a new paradigm to treat lung cancer, most significantly after it has spread to the brain

Therefore, the authors theorized that GABA(A) receptor activation could improve tumor control for human cancer patients, and allow for lower radiation doses, lessening toxicity.

“GABA(A) receptors have been a key pharmacologic target to remediate neurological disorders for over 70 years,” the authors wrote. “In this study, we demonstrate that activating GABA(A) receptors can be leveraged to effectively treat primary NSCLC and its brain metastases when used in combination with radiation.”

The research team is currently working toward phase 1 clinical trials for its discovery, with plans to test the combination of AM-101 and radiation both in lung cancer within the lungs and lung cancer that has spread to the brain.