In new research, a team led by University of Cincinnati researchers has identified a potential new way to make radiation more effective and improve outcomes for patients with lung cancer that has spread to the brain.
The study, led by first author Debanjan Bhattacharya, PhD, was recently published in the journal Cancers.
Research background
According to the American Cancer Society, lung cancer is the leading cause of cancer deaths in the United States, accounting for approximately one in five cancer deaths. Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer, accounting for approximately 80% to 85% of all lung cancer cases.
Up to 40% of lung cancer patients develop brain metastases during the course of the disease and these patients survive on average eight to 10 months after diagnosis.
Current standard treatments for lung cancer that has spread to the brain include surgical resection and stereotactic brain radiosurgery, and whole brain irradiation is standard in patients with more than 10 metastatic brain lesions.
“Brain metastasis from lung cancer is usually incurable and treatment with whole-brain radiation is palliative, as radiation limits therapy due to toxicity,” said Bhattacharya, a research instructor in the Department of Neurology and Medicine at Rehabilitation of the UC School of Medicine. “Managing potential side effects and overcoming radiation resistance are major challenges when treating brain metastases from lung cancer. This highlights the importance of new treatments that are less toxic and can improve the effectiveness of radiotherapy, are less expensive and can improve the quality of life in patients.”
Research focus
Bhattacharya and his UC colleagues focused on AM-101, a synthetic analogue of the benzodiazepine class first developed by James Cook, a medicinal chemist at the University of Wisconsin-Milwaukee. Before this study, the effect of AM-101 on non-small cell lung cancer was unknown.
AM-101 is a particularly useful drug in the setting of brain metastases in NSCLC, Bhattacharya said, since benzodiazepines are known to be able to cross the blood-brain barrier that protects the brain from potential harmful invaders that some drugs can also block. reaching its target in the brain.
Research results
The team found AM-101-activated GABA(A) receptors located on NSCLC cells and metastatic lung cancer brain cells. This activation triggers the “eating itself” process of autophagy where the cell recycles and degrades unwanted cell parts.
Specifically, the study demonstrated that activation of GABA(A) receptors increases the expression and clustering of GABARAP and Nix (an autophagy receptor), which drives the autophagy process in lung cancer cells. This enhanced “eating yourself” autophagy process makes lung cancer cells more sensitive to radiation treatment.
Using animal models of lung cancer brain metastases, the team found that AM-101 makes radiation treatment more effective and significantly improves survival. Additionally, the drug was found to slow the growth of primary NSCLC cells and brain metastases.
In addition to making radiation more effective, adding AM-101 to radiation treatments could allow for lower radiation doses, which could reduce side effects and toxicity for patients, Bhattacharya said. The team is now working to open Phase 1 clinical trials testing the combination of AM-101 and radiation in both lung cancer within the lungs and lung cancer that has spread to the brain.
Bhattacharya began this research while working in the lab of former UC researchers Soma Sengupta and Daniel Pomeranz Krummel, who are now at the University of North Carolina at Chapel Hill. Bhattacharya credits his mentorship and collaboration with other experts within UC and at multiple academic research institutions in the United States.
Bhattacharya also emphasizes the role of shared university research resources that helped the study move forward. He dedicates this work to his father, who died in 2021 while he was in the early phases of the research.
“All work, along with the review experiments, was performed at the University of Cincinnati, and this reflects the strong collaborative effort between multiple teams. I thank the Department of Neurology and Rehabilitation Medicine for the overall support in completing this study. ” said. “My father’s passing motivated me to work harder to complete this project, as he knew about my research and wanted to see me succeed.”