Year: 2015
Type: article
Abstract: The recent publication by Huang et al. identifies the EAG2 (Ether-a-go-go 2) potassium channel as a new regulator of tumor growth and metastasis and therapeutic target in drosophila brain tumors and human medulloblastoma. The authors argue that more than 20% of drugs used for treating human diseases target ion channels, but no cancer drug approved by the US Food and Drug Administration (FDA) is intended to target an ion channel. To address this apparent disparity, they first show that Drosophila Eag promotes tumor growth and metastasis in three Drosophila brain tumor models. They then perform cross-species transcriptomic studies to delineate common pathways regulated by the EAG2/Eag potassium channels and find that EAG2 and its downstream KCNT2 potassium channel cooperate in the regulation of medulloblastoma mitotic cell volume and cell proliferation. They observe that the EAG2 channel is enriched at the trailing edge of migrating medulloblastoma cells to regulate local cell volume dynamics and enhance cell motility. Importantly, they also demonstrate that knockdown of EAG2 expression inhibits metastasis in a medulloblastoma xenograft model. To identify EAG2-blocking agents as potential medulloblastoma therapeutics, the authors then screened a series of HERG channel–blocking FDA-approved antipsychotics for their efficacy in inhibiting medulloblastoma cell growth. HERG was chosen because of its structural similarity to EAG2. Using this approach, they identify the FDA-approved antipsychotic drug thioridazine (Mellaril) as an EAG2 channel blocker. They show that thioridazine treatment potently inhibits medulloblastoma cell viability and motility and reduces intracranial medulloblastoma xenograft growth and metastasis. The authors then analyzed human medulloblastoma tumor specimens and found that EAG2 was upregulated in a subset of medulloblastoma metastases compared with the matched primary tumors from the same patients. Finally, they presented a case report of repurposing thioridazine to treat a human patient with metastasized medulloblastoma with encouraging (albeit limited and temporary) anti-metastasis effects.
Source: Neuro-Oncology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4239154896