According to a recent study published in the journal Proceedings of the National Academy of Sciences by the University of Pittsburgh, the malaria drug hydroxychloroquine could be used to treat head and neck cancers that are resistant to chemotherapy. The researchers behind this study found that the drug could be used to inhibit the pathways that cause resistance to a chemotherapy agent called cisplatin.
The researchers are optimistic about these findings and a second clinical trial has been scheduled. Here’s what you need to know:
Chemotherapy Resistance in Head and Neck Cancers
According to study co-senior author Umamaheswar Duvvuri, MD, PhD, chemotherapy often fails as a treatment method for patients with head and neck cancers. This failure is because of tumor resistance to an important chemotherapy drug called Cisplatin. Duvvuri’s lab at the Pitt School of Medicine has been working to understand these resistance mechanisms with the goal of finding better treatment methods for head and neck cancer patients.
According to another study in the American Journal of Cancer Research, resistance to cisplatin and other drugs like cetuximab is one of the biggest obstacles in the treatment of head and neck cancers. The Pitt researchers are optimistic that using hydroxychloroquine to combat cisplatin resistance could potentially result in improved outcomes for head and neck cancer patients.
Previous Research on Cisplatin Resistance
Past research indicates that a protein called TMEM16A is associated with cisplatin resistance. About 30 percent of head and neck cancer patients exhibit overexpression of this protein, which is also linked to lower survival rates. TMEM16A is part of a protein group known as ion channels, which lie in the outer envelope of the cell.
Chloride ions are responsible for the regulation of muscle and nerve activation and transporting salt and water and they pass through the TMEM16A proteins. Problems with chloride transportation have previously been linked to neurological and kidney diseases, including epilepsy and cystic fibrosis.
Pitt School of Medicine Findings on TMEM16A
The Pitt study found that TMEM16A can facilitate the expulsion of cisplatin in cellular compartments called lysosomes. Lysosomes normally recycle and dispose of waste by breaking molecules down to reuse them and expel cellular detritus. However, in tumors that show overexpression of TMEM16A, the protein promotes increased lysosome production. These lysosomes are used to discharge cisplatin from the cell.
Essentially, these findings show that cancer cells use an active mechanism to expel chemotherapy drugs from the patient’s system. The researchers took a deep dive into this process and conducted extensive research to understand the fundamentals of the process.
Methodology of the Hydroxychloroquine Study
After identifying TMEM16A as a critical node, the researchers began testing to determine if hydroxychloroquine could be used to disrupt this process and whether this anti-malarial agent could be used as a form of cancer treatment. Hydroxychloroquine inhibits the function of lysosomes.
To test whether this same effect could be beneficial in the treatment of cisplatin-resistant cancers, the researchers implanted human cancer cells into fertilized chicken eggs. The agent was directed into the membrane encompassing the embryo. Their findings indicated that the eggs treated with both cisplatin and hydroxychloroquine showed higher tumor cell death rates compared to those only treated with cisplatin.
The team of researchers also conducted tests on mice with tumors derived from cisplatin-resistance human cancer cells. The results were similar, as the combination treatment of cisplatin and hydroxychloroquine reduced tumor growth more than the use of either of the compounds separately.
Further Pitt Research into Hydroxychloroquine
Duvvuri and his team believe that these findings show a synergy between cisplatin and hydroxychloroquine. Additionally, because hydroxychloroquine is already on the market as a malaria drug, the researchers should be able to expedite the investigation of these findings in clinical trials compared to the standard timeline for novel compounds.
The same team of researchers is currently planning a phase 2 clinical trial, in which the cisplatin and hydroxychloroquine combination will be tested on head and neck cancer patients. The team hopes to see the same encouraging results they found in the chicken egg and mice experiments.
Other Clinical Trials on Hydroxychloroquine
The University of Pittsburgh School of Medicine is not the only institution exploring how hydroxychloroquine can be used in cancer treatment. According to the National Cancer Institute, there are several current clinical trials involving the anti-malaria drug:
A Phase I trial is seeking to determine the maximum tolerated dose of hydroxychloroquine when combined with devimistat in patients with relapsed or refractory clear cell sarcomas of soft tissue.
A Phase II trial is investigating the effectiveness of hydroxychloroquine combined with chemotherapy drugs gemcitabine and nab-paclitaxel in the treatment of metastatic pancreatic cancer patients.
A Phase II trial is studying the effects of metastatic breast cancer drug abemaciclib when used on its own and in combination with hydroxychloroquine.
These are just a handful of the many ongoing clinical trials investigating multiple uses of hydroxychloroquine in cancer treatment. We look forward to the results of the University of Pittsburgh’s upcoming clinical trial, along with the findings of other institutions studying the effectiveness of this drug in oncology.