Umamaheswar Duvvuri, MD, Ph.D., FACS, Professor, Department of Otolaryngology at UPMC and the VA Pittsburg Health System. In this video, he speaks about the article Malaria drug could help treat chemotherapy-resistant head and neck cancers.
According to a new study, the malaria medicine hydroxychloroquine blocks mechanisms that develop resistance to the chemotherapeutic agent cisplatin in head and neck tumors and restores cisplatin’s tumor-killing properties in animal models.
The findings, reported today in the Proceedings of the National Academy of Sciences by scientists from the University of Pittsburgh and UPMC, clear the way for a clinical study combining cisplatin and hydroxychloroquine to treat chemotherapy-resistant head and neck tumors.
A previous study has connected a protein called TMEM16A to cisplatin resistance in patient malignancies. Overexpression of this protein, which occurs in around 30% of head and neck malignancies, is likewise linked to a worse chance of survival.
TMEM16A is a member of the ion channel protein family. These proteins, which straddle the cell’s outer envelope, provide a pathway for chloride ions, which govern muscle and nerve activity as well as salt and water transport. Duvvuri was astonished by the association between TMEM16A and cancer because poor chloride transport is normally associated with neurological and kidney illnesses such as epilepsy, cystic fibrosis, and kidney stones.
According to the current research, TMEM16A enhances cisplatin ejection in cellular compartments known as lysosomes. Lysosomes in a healthy cell function as a recycling and waste disposal mechanism, breaking down molecules for reuse and eliminating cellular debris.
According to first author Avani Vyas, Ph.D., postdoctoral associate at Pitt, in cancers that overexpress TMEM16A, this protein triggers a new signaling pathway, increasing the formation of lysosomes, which trap and expel cisplatin from the cell.
The anti-malarial drug hydroxychloroquine suppresses lysosomal function. The team first transplanted human cancer cells onto the membrane covering the embryo in fertilized chicken eggs to assess its potential to treat cisplatin-resistant malignancies.
They discovered that eggs treated with both hydroxychloroquine and cisplatin showed more tumor cell killing than eggs treated only with cisplatin.
Similarly, the combination of hydroxychloroquine and cisplatin reduced tumor growth more than either chemical alone in mice with tumors originating from cisplatin-resistant human cancer cells.
The researchers are now planning a phase II clinical trial using hydroxychloroquine plus cisplatin to treat individuals with head and neck cancer.