Editors' ChoiceCancer

Channeling brain cancer

Sci. Signal.  01 Sep 2015:
Vol. 8, Issue 392, pp. ec245
DOI: 10.1126/scisignal.aad3213

Medulloblastoma is a common pediatric brain cancer with few treatment options. Huang et al. found that a clinically approved antipsychotic drug that inhibits the potassium ion channel EAG2 may slow medulloblastoma growth and progression. Transcript analysis of medulloblastoma patient tissue revealed greater EAG2 expression in metastatic lesions and less KCNT2 expression in a subtype of the primary tumor. Pathway analysis of transcriptomic profiles from human medulloblastoma cell lines revealed that loss of EAG2 was associated with impaired kinase signaling, mitotic cell cycling, and cell survival. Cells in which EAG2 was knocked down had less abundance of KCNT2, a potassium channel that is activated by intracellular sodium and chloride. Knocking down or pharmacologically inhibiting KCNT2 slowed tumor growth and prolonged survival of mice bearing human medulloblastoma xenografts. Manipulating EAG2 and KCNT2 expression in medulloblastoma or COS7 cells revealed that EAG2 and KCNT2 decreased cell volume at different stages in the cell cycle, enabling mitotic progression and cell morphology changes. Knocking down EAG2 in human medulloblastoma cells before implantation into mice prevented dissemination and metastasis. EAG2 abundance was enriched at the trailing edge of migrating cells, and EAG2 knockdown or pharmacological inhibition with the antihistamine drug astemizole reduced cell motility and impaired polarization and rear contraction. Through a drug screen, the authors found that the clinically approved antipsychotic thioridazine reduced the proliferation and migration of medulloblastoma cells in culture. Intraperitoneal injection of thioridazine induced regression of the primary tumor and prevented metastasis in mice bearing established medulloblastoma cell line–derived xenograft cranial tumors that had a high abundance of EAG2. In a patient with widespread metastatic medulloblastoma receiving palliative chemotherapy, treatment with thioridazine induced regression in an iliac lesion that exhibited high EAG2 abundance. Although there were no adverse cardiac effects, prolonged thioridazine triggered severe emotional instability and depression that required cessation of the therapy. Thus, repurposing thioridazine for medulloblastoma effectively treats the tumor, but further drug development to target EAG2 is needed to treat the tumor without damaging the patient’s quality of life.

X. Huang, Y. He, A. M. Dubuc, R. Hashizume, W. Zhang, J. Reimand, H. Yang, T. A. Wang, S. J. Stehbens, S. Younger, S. Barshow, S. Zhu, M. K. Cooper, J. Peacock, V. Ramaswamy, L. Garzia, X. Wu, M. Remke, C. M. Forester, C. C. Kim, W. A. Weiss, C. D. James, M. A. Shuman, G. D. Bader, S. Mueller, M. D. Taylor, Y. N. Jan, L. Y. Jan, EAG2 potassium channel with evolutionarily conserved function as a brain tumor target. Nat. Neurosci. 18, 1236–1246 (2015). [PubMed]