“The research was personal as it was carried out in honor of my mother-in-law, Rifke Krummel, and my close friend and fellow neuro-oncologist Tara Benkers.” – Dr. Soma Sengupta

UNC Neurosurgery faculty members Dr. Soma Sengupta and Dr. Daniel Pomeranz Krummel are co-authors of a new publication in Cancers that reports on a new way to target lung cancer that has metastasized, or spread, to the brain.

Lung cancer is a leading cause of cancer associated mortality. Most lung cancer patients will clinically present with metastatic disease, which is usually incurable. A particularly challenging metastatic site to treat is the brain. The current standard of care for lung cancer in the brain includes surgical resection and stereotactic brain radiosurgery in most cases. Unfortunately, even with standard of care treatment, survival is less than a year. An urgent solution is needed to treat metastatic disease that is more effective, less expensive, and does not impact quality of life, but also enhances survival.

Dr. Sengupta, Dr. Pomeranz Krummel, and colleagues demonstrated that lung cancer cells possess GABA(A) receptors, which form channels in the cell membrane in the cancer cells to move chloride ions out of the cell. Importantly, they have also shown that the GABA(A) receptors in cancer cells work differently than receptors in mature normal cells. These observations suggested that GABA(A) receptors may be a vulnerability to the cancer cells in the brain that can be leveraged for treatment. Their research set out to explore this possibility.

Collaborating with colleagues from various academic centers in the U.S. with needed expertise in bioengineering, pharmacy, medicinal and bioorganic chemistry, and radiation physics, first author of the paper Dr. Debanjan Bhattacharya, Dr. Sengupta, and Dr. Pomeranz Krummel explored if enhancing GABA(A) receptors with a synthetic activator could potentiate radiotherapy to treat lung cancer in the brain. Significantly, they found that by activating the receptor, radiation treatment was much more effective leading to increased control of tumor growth, and mice bearing the tumors lived longer symptom-free.

The researchers than explored how this all worked, finding that activation of GABA(A) receptors created a pronounced bioelectric imbalance in the cancer cells that triggered dramatic changes in protein interactions that culminated in autophagy, an ‘auto-eating’ phenomenon.

This work was the culmination of studies started by Dr. Sengupta when she was an attending at Beth Israel Deaconness Medical Center in Boston. At the time she was studying a pediatric brain cancer called medulloblastoma. Teaming up with Dr. Pomeranz Krummel and a senior medicinal chemist at the University of Wisconsin-Milwaukee, Dr. Jim Cook, they have shown that many cancers can be treated by targeting intrinsic GABA(A) receptors in cancer cells.

In 2020 Dr. Pomeranz Krummel’s mother had a fall and then an MRI to check her brain. The MRI revealed numerous tumors in her brain from a lung cancer that she thought she had successfully fought. She immediately received radiotherapy to her brain. Tragically, within a week of radiation treatment she had changed cognitively and within a few months, passed away. The choice of pursuing this research was personal and driven by finding a solution to treat metastatic disease that is more effective, less expensive, and does not impact quality of life but enhances survival. “The research was personal as it was carried out in honor of my mother-in-law, Rifke Krummel, and my close friend and fellow neuro-oncologist Tara Benkers,” said Dr. Sengupta. “Working with Dr. Debanjan Bhattacharya and team members and colleagues at the University of Cincinnati to finish the project while Dr. Pomeranz Krummel and I were moving to UNC made it a highly collaborative endeavor between the two institutions.”

About Dr. Soma Sengupta and Dr. Daniel Pomeranz Krummel
Dr. Soma Sengupta is a Professor of Neurosurgery and Neurology, Division Chief of Neuro-oncology, and Vice Chair of Research in the Department of Neurosurgery. She is a clinical trialist specializing in brain tumor treatment and patient care as well as a researcher with over 90 publications on clinical trials, case reports, lab-based research, and healthcare policy. Dr. Sengupta and Dr. Daniel Pomeranz Krummel, a faculty member in the Department of Neurosurgery at UNC Health, collaborate closely in research  on the development of approaches to improve treatment of malignant brain tumors, both primary and metastatic, and improve patient outcomes. Both Dr Sengupta and Dr. Pomeranz Krummel are members of the UNC Lineberger Comprehensive Cancer Center.