“, said co-author Umamaheswar Duvvuri, MD, PhD, head and neck surgeon at UPMC Hillman Cancer Center and professor of otolaryngology at the Pitt School of Medicine.
“My lab is interested in understanding the mechanism of resistance so we can find better ways to treat these patients.. ”
Previous research has shown that a protein called TMEM16A is involved in 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 known as ion channels. Wrapped tightly in the cell’s outer shell, these proteins provide pathways for chloride ions, which help regulate muscle and nerve activation and salt and water transport.
Since impaired chloride transport is commonly associated with neurological and kidney diseases such as epilepsy, cystic fibrosis, and kidney stones, Duvvuri was surprised at the link between TMEM16A and cancer.
“It’s always been a bit confusing, he says, as to why an ion channel is upregulated in cancer.. ”
New research shows that TMEM16A promotes cisplatin expulsion in cell compartments called lysosomes. In a healthy cell, the lysosome acts like a recycling and waste disposal system, breaking down molecules for reuse and removing cellular debris.
According to first author Avani Vyas, PhD, postdoctoral associate at Pitt, in tumors overexpressing TMEM16A, this protein promotes a novel signaling pathway, promotes lysosome production, sequestering and remove cisplatin from the cell.
“We show that cancer cells have a mechanism of action to eliminate chemotherapeutic drugs“, co-author Kirill Kiselyov, PhD, associate professor of biological sciences at Pitt, added.After analyzing this process at the basal level and identifying TMEM16A as a critical node, the next step was to test whether disrupting this process with hydroxychloroquine might have translational potential.. ”
Hydroxychloroquine is an antimalarial that inhibits lysosome function. To evaluate the potential for treatment of cisplatin-resistant cancers, the team first implanted human cancer cells onto the membrane surrounding embryos in fertilized chicken eggs.
They found that eggs treated with both hydroxychloroquine and cisplatin had higher rates of tumor cell death than those 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 more than either compound.
“These experiments show that hydroxychloroquine has a synergistic effect with cisplatin,“Duvvuri explained.”This is relevant for patients because replacing hydroxychloroquine, which is an existing drug, would allow us to get these findings to the clinic much faster than we could with a new compound.”
Researchers are currently designing a phase II clinical trial to treat patients with head and neck cancer with a combination of hydroxychloroquine and cisplatin.
Source: Medindia
