title: Administration of Non-Torsadogenic human Ether-à-go-go-Related Gene Inhibitors Is Associated with Better Survival for High hERG-Expressing Glioblastoma Patients.
abstract: OBJECTIVE
  Glioblastoma is the most malignant primary brain tumor, with a median survival of less than 2 years. More effective therapeutic approaches are needed to improve clinical outcomes.
  
  
  METHODS
  Glioblastoma patient-derived cells (GPDC) were isolated from patient glioblastomas and implanted in mice to form xenografts. IHC was performed for human Ether-à-go-go-Related Gene (hERG) expression and tumor proliferation. Sphere-forming assays with the hERG blocker E-4031 were performed on a high and low hERG-expressing lines. A glioblastoma tissue microarray (TMA; 115 patients) was used to correlate hERG expression with patient survival. Clinical data were analyzed to determine whether patient survival was affected by incidental administration of hERG inhibitory drugs and the correlative effect of patient glioblastoma hERG expression levels.
  
  
  RESULTS
  hERG expression was upregulated in glioblastoma xenografts with higher proliferative indices. High hERG-expressing GPDCs showed a reduction in sphere formation when treated with hERG inhibitors compared with low hERG-expressing GPDCs. Glioblastoma TMA analysis showed worse survival for glioblastoma patients with high hERG expression versus low expression-43.5 weeks versus 60.9 weeks, respectively (P = 0.022). Furthermore, patients who received at least one hERG blocker had a better survival rate compared with patients who did not (P = 0.0015). Subgroup analysis showed that glioblastoma patients with high hERG expression who received hERG blockers had improved survival (P = 0.0458). There was no difference in survival for low hERG-expressing glioblastoma patients who received hERG blockers (P = 0.4136).
  
  
  CONCLUSIONS
  Our findings suggest that hERG is a potential glioblastoma survival marker, and that already approved drugs with non-torsadogenic hERG inhibitory activity may potentially be repurposed as adjuvant glioblastoma therapy in high hERG-expressing glioblastoma patients. Clin Cancer Res; 23(1); 73-80. ©2016 AACRSee related commentary by Arcangeli and Becchetti, p. 3.
authors.affiliation: Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.|Medical Scientist Training Program, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.|Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, Wisconsin.|Laboratory for Optical and Computational Instrumentation (LOCI), University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Kelli B
authors.initials: KB
authors.lastname: Pointer
authors.affiliation: Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clark
authors.affiliation: Laboratory for Optical and Computational Instrumentation (LOCI), University of Wisconsin-Madison, Madison, Wisconsin.|Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Eliceiri
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: M Shahriar
authors.initials: MS
authors.lastname: Salamat
authors.affiliation: Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin. j.kuo@neurosurgery.wisc.edu garobert@wisc.edu.|Cardiovascular Research Center, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Gail A
authors.initials: GA
authors.lastname: Robertson
authors.affiliation: Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin. j.kuo@neurosurgery.wisc.edu garobert@wisc.edu.|Medical Scientist Training Program, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.|Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, Wisconsin.|Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.|Department of Surgery, National University of Singapore, Singapore.
authors.forename: John S
authors.initials: JS
authors.lastname: Kuo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005909:Glioblastoma / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051379:Mice; D058990:Molecular Targeted Therapy; D010880:Piperidines / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D018874:Spheroids, Cellular; D046888:Tissue Array Analysis; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051638:Ether-A-Go-Go Potassium Channels; D010880:Piperidines; D011725:Pyridines; C063968:E 4031