Common class of channel blockers may find a role in cancer therapy
Ion channel blockers, drugs commonly used to treat cardiac, neurologic, and psychiatric disorders, might prove useful in cancer therapy, according to research findings in fruit flies and mice. These findings, published in Nature Neuroscience (2015; doi:10.1038/nn.4088), led to unconventional treatment of a case of metastatic brain cancer.
Ion channels, proteins that form pores in cell membranes, play central roles in organs in which conduction of electrical signals is vital, such as the brain and heart, but they are found in cells throughout the body. Approximately 20% of FDA-approved medications target ion channels because the location of these proteins at the cell surface makes them especially druggable. However, no channel blockers have been approved for cancer treatment.
However, a drug that blocks channels that allow potassium ions to move out of cells was effective in slowing the growth of medulloblastoma, a type of brain cancer, that had metastasized to the bones in the pelvis of a young patient. The drug in question, thioridazine, was originally developed to treat psychosis, but is now rarely used due to significant side effects.
"We showed that blocking a specific ion channel in medulloblastoma can impede tumor cells from proliferating and spreading," said Lily Jan, PhD, a Howard Hughes Medical Institute (HHMI) investigator and professor of physiology at University of California San Francisco, and a senior scientist on the research team.
"The development of a drug designed to act on this newly identified target more specifically and more powerfully, with fewer side effects, would have the potential to improve outcomes for many with this disease, which is a common cause of death in children."
The rationale for the unusual treatment had its roots in research begun approximately 5 years ago by former UCSF postdoctoral fellows Xi Huang, PhD, now at the University of Toronto's Hospital for Sick Children, and Ye He, PhD, of UCSF.
The UCSF team collaborated with scientists at the Hospital for Sick Children and the University of Toronto to show that both the fruit fly version of the ion channel protein EAG2 and human EAG2 act in concert with another ion channel, KCNT2, to promote tumor growth.
Huang also discovered that changes in EAG2 abundance at the trailing edge of migrating tumor cells alter cell volume and shape, and enable tumor cells to more easily move and spread. When he transplanted EAG2-producing human medulloblastoma tissue into mice, he found that thioridazine inhibited tumor growth and metastasis. Huang's presentations of this work at campus seminars led to the team's collaborations with medical colleagues and, eventually, to treatment of the patient at UCSF Medical Center.
Surgery, radiation, and chemotherapy, as well as experimental treatments, were no longer effective in arresting growth of widespread metastases in the patient, whose medulloblastoma was originally diagnosed when the patient was a teenager.
But after thioridazine treatment, UCSF physicians, including pediatric oncologist Sabine Mueller, MD, PhD, of the Helen Diller Family Comprehensive Center, observed shrinkage of an EAG2-expressing metastatic tumor in the patient's pelvis. The patient could not tolerate thioridazine's side effects, however, and he succumbed to the disease several months after ending a 2-month course of the drug.