• John S Kuo, Kelli Briana Pointer, Paul A Clark, and Gail Robertson.
• Neurosurgery. 2015 Aug 1;62 Suppl 1:210-1.

IntroductionHuman ether a go-go-related-1 (hERG) is a voltage-dependent K+ channel overexpressed in GBM cell lines, and linked to aberrant proliferation. The FDA mandates all drugs undergo cardiotoxicity profiling that includes hERG inhibition. We analyzed hERG expression in glioblastoma stemlike cell (GSC)-derived tumor models and a clinically annotated human GBM tissue microarray (TMA) to correlate with patient survival after hERG expression stratification.MethodsPatient-derived GSC lines were isolated, validated with multipotent differentiation and orthotopic xenograft formation in NOD-SCID mice. Immunohistochemistry on tumor xenograft paraffin-embedded sections for hERG expression and tumor proliferation performed. Tumor sphere drug sensitivity assays with hERG blockers (E-4031, phenytoin) were performed using multiple low hERG-expressing and high hERG-expressing GSC lines. A GBM TMA of 115 patients linked to clinical data was used to correlate hERG expression levels with patient survival, and interrogate effects of hERG inhibition drugs.ResultsGBM xenografts with a higher Ki-67 proliferative index show hERG overexpression. High hERG-expressing GSC lines showed a 50% reduced sphere formation when treated with hERG inhibitors (IC50: phenytoin 7.7 nM, E-4031 100 μM). GBM TMA analysis showed significantly worse survival for high hERG expression GBM patients vs low hERG expression (P = .0168). Receipt of one or more hERG blocker drugs improved GBM patient survival (P = .0004). The subgroup of high hERG expression GBM patients who received a hERG blocker enjoyed significantly better survival (P = .0495). There was no drug-related survival difference for low hERG-expressing GBM patients (P = .5482).ConclusionWe showed that GBM xenografts with higher hERG expression had higher proliferation rates, and the addition of 2 known hERG inhibitors (phenytoin, E-4031) inhibited sphere formation in high hERG-expressing GSC lines. GBM TMA analyses showed significantly better survival in high hERG-expressing GBM patients treated with hERG inhibitory drugs. These data suggest clinical trials for already FDA-approved drugs that also inhibit hERG in high hERG-expressing GBM patients.

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