A new study has suggested that the commonly used malaria drug hydroxychloroquine blocks pathways that drive resistance to the chemotherapy drug cisplatin in head and neck cancers, according to Medical Xpress.
The study, published in Proceedings of the National Academy of Sciences by the University of Pittsburgh and UPMC scientists, has also found that hydroxychloroquine restores tumor-killing effects of cisplatin in animal models.
These findings could pave the way for human trials to study the effects of the combination of cisplatin and hydroxychloroquine to treat chemotherapy-resistant head and neck cancers.
The study’s co-senior author Dr. Umamaheswar Duvvuri said, “When caring for patients with head and neck cancers, I often see chemotherapy fail. Cisplatin is a very important chemotherapy drug, but tumor resistance to cisplatin is a huge problem. My lab is interested in understanding the mechanisms of resistance so that we can find better ways to treat these patients.”
Earlier studies have shown that a protein known as TMEM16A is associated with cisplatin resistance in tumors. Also, overexpression of this protein is linked to decreased survival.
The new study suggests that TMEM16A promotes expulsion of the chemo drug cisplatin in cellular compartments called lysosomes. In healthy cells, lysosomes act like a recycling and waste disposal system, which further breaks down molecules for reuse and expelling cellular detritus.
The study’s first author Dr. Avani Vyas said in tumors that overexpress TMEM16A, this protein drives a novel signaling pathway, boosting the production of lysosomes, which sequester and expel cisplatin from the cell.
Dr. Kirill Kiselyov, another co-senior author, said, “We show that cancer cells have an active mechanism to discard chemotherapeutic drugs. After dissecting this process on a fundamental level and identifying TMEM16A as a critical node, the next step was to test whether disrupting this process with hydroxychloroquine could have translational potential.”
Sold under the brand name Plaquenil, hydroxychloroquine inhibits lysosomal function. The researchers found that eggs treated with hydroxychloroquine and cisplatin had greater tumor cell death than those treated with cisplatin alone, per Medical Xpress.
Similarly, the combination of hydroxychloroquine and cisplatin slowed tumor growth in mice with tumors derived from cisplatin-resistant human cancer cells.
The team is now designing a clinical trial to treat head and neck cancer patients with both hydroxychloroquine and cisplatin.
Dr. Duvvuri said, “These experiments suggest that hydroxychloroquine has a synergistic effect with cisplatin. This is relevant for patients because repurposing hydroxychloroquine, which is an existing drug, will allow us to translate these findings to the clinic much faster than we could with a novel compound.”
