Study finds importance of malaria drug in treating neck cancers


The findings, published in the Proceedings of the National Academy of Sciences by scientists at the University of Pittsburgh and UPMC, pave the way for clinical trials that combine cisplatin and hydroxychloroquine to treat chemotherapy-resistant head and neck cancer.

“When treating patients with head and neck cancer, I often see that chemotherapy does not work. Cisplatin is a very important chemotherapy drug, but tumor resistance to cisplatin is a huge problem,” said co-author Umamaheswar Duvvuri, MD, chief and neck surgeon at UPMC Hillman Cancer Center and professor of otolaryngology at Pitt Medical School. “My lab is interested in understanding the mechanisms of resistance so we can find better ways to treat these patients,” Umamaheswar added. Previous research has shown that a protein called TMEM16A is associated with cisplatin resistance in patients’ tumors. Overexpression of this protein, which occurs in about 30% of head and neck cancers, is also associated with reduced survival. TMEM16A belongs to a group of proteins called ion channels. Located on the outer shell of the cell, these proteins provide a passageway for chloride ions, which regulate muscle and nerve activation, as well as the transport of salt and water. Because impaired chloride transport is commonly associated with neurological and renal diseases such as epilepsy, cystic fibrosis, and kidney stones, Duvvuri was surprised by the link between TMEM16A and cancer.

“It’s always been a bit of a mystery why an ion channel gets activated in cancer,” he said. “This study provides important clues to solve this puzzle.” The new study suggests that TMEM16A promotes the clearance of cisplatin from cellular compartments called lysosomes. In a healthy cell, lysosomes act as a recycling and waste disposal system, breaking down molecules for reuse and removing cellular debris. cell, according to first author Avani Vyas, Ph.D., a postdoctoral fellow of Pitt.

“We show that cancer cells have an active mechanism for rejecting chemotherapy drugs,” added co-author Kirill Kiselev, Ph.D., Associate Professor in the Pitt Department of Biological Sciences. “After analyzing this process at a fundamental level and identifying TMEM16A as a critical node, the next step was to test whether disrupting this process with hydroxychloroquine could have a translational potential.” To assess its potential in treating cisplatin-resistant cancer, the team first implanted human cancer cells into the membrane surrounding the embryo in fertilized chicken eggs. They found that eggs treated with both hydroxychloroquine and cisplatin had greater tumor cell death than eggs treated with cisplatin alone. Similarly, in mice with tumors derived from cisplatin-resistant human cancer cells, the combination of hydroxychloroquine and cisplatin slowed tumor growth to a greater extent than either compound alone.

“These experiments show that hydroxychloroquine has a synergistic effect with cisplatin,” Duvvuri explained. “This is important for patients because reusing hydroxychloroquine, which is an existing drug, will allow us to bring these findings to the clinic much faster than we could with the new compound.” Researchers are currently developing a phase II clinical trial to treat patients with head and neck cancer with a combination of hydroxychloroquine and cisplatin.

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