Highly druggable ion channels, which are common therapeutic targets for heart disease and neurological conditions, may represent useful targets in cancer treatment as well, according to researchers from the University of California at San Francisco.
Highly druggable ion channels, which are common therapeutic targets for heart disease and neurological conditions, may represent useful targets in cancer treatment as well, according to researchers from the University of California at San Francisco (UCSF).1 Recent findings show the human ether a-go-go potassium channel 2 (EAG2) helped to regulate medulloblastoma cell proliferation, and the presence of EAG2 enhanced metastatic potential of the tumor cells by increasing cell motility.2
Medulloblastoma (MB) is the most common pediatric malignant primary brain tumor. The noninvasive, rapidly growing tumor spreads through the cerebrospinal fluid and frequently metastasizes to locations along the surface of the brain and spinal cord. MB metastases are clinically and genetically distinct from matched primary tumors and likely require therapy specific for metastatic cells.
“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,” said Lily Jan, PhD, professor of physiology at UCSF School of Medicine and research team leader, in a UCSF press release.
The team screened a series of antipsychotic channel blockers for efficacy in inhibiting MB cell growth. They found that the US Food and Drug Administration (FDA)-approved drug thioridazine blocks EAG2, and the drug reduced MB growth and metastasis in intracranial xenografts in mice. Treating MB cells with other selective human ether-a-go-go-related gene (hERG) channel blockers that did not block EAG2 had little effect on MB cell growth.
A case report of a 22-year-old male patient with metastatic MB and high EAG2 expression in an iliac lesion showed clinical efficacy for thioridazine. Thioridazine was added to a palliative chemotherapy regimen for approximately 2 months. After the thioridazine treatment, the iliac lesion was reduced, suggestive of a response to therapy.
“The results seen in our patient are encouraging for targeting EAG2 channel as a potential therapy in MB. However, we emphasize caution given the singular case described here and considerable potential side effects that could affect tolerance of thioridazine,” the researchers noted.
In order to demonstrate the role of EAG2 in MB, the investigators focused their efforts on Drosophila, a common model for studying brain tumors. They developed brain tumor models with deficiency in the fly ortholog of EAG2, which hindered tumor growth and reduced metastasis.
In human MB cells implanted in mice, most tumors metastasized within several weeks (56% intracranial and 67% spinal cord). However, mice bearing implanted MB tumors with EAG2 knockdown displayed no metastasis after several months.
Quantitative PCR of both primary tumors and metastatic nodules in humans showed that metastatic MB cells had a higher likelihood for upregulation of EAG2 (greater than 1.5 fold) compared with matched primary tumors. This finding suggests that EAG2 may promote metastasis or tumor growth at the disseminated site.
The team speculated that blocking the EAG2 channel likely impacts both mitosis and cell motility of tumor cells.