Sodium ion channel mutations in glioblastoma patients correlate with shorter survival

Avadhut D Joshi,Victor E Velculescu,D Williams Parsons,Gregory J Riggins

doi:10.1186/1476-4598-10-17

Abstract

BackgroundGlioblastoma Multiforme (GBM) is the most common and invasive astrocytic tumor associated with dismal prognosis. Treatment for GBM patients has advanced, but the median survival remains a meager 15 months. In a recent study, 20,000 genes from 21 GBM patients were sequenced that identified frequent mutations in ion channel genes. The goal of this study was to determine whether ion channel mutations have a role in disease progression and whether molecular targeting of ion channels is a promising therapeutic strategy for GBM patients. Therefore, we compared GBM patient survival on the basis of presence or absence of mutations in calcium, potassium and sodium ion transport genes. Cardiac glycosides, known sodium channel inhibitors, were then tested for their ability to inhibit GBM cell proliferation.ResultsNearly 90% of patients showed at least one mutation in ion transport genes. GBM patients with mutations in sodium channels showed a significantly shorter survival compared to patients with no sodium channel mutations, whereas a similar comparison based on mutational status of calcium or potassium ion channel mutations showed no survival differences. Experimentally, targeting GBM cells with cardiac glycosides such as digoxin and ouabain demonstrated preferential cytotoxicity against U-87 and D54 GBM cells compared to non-tumor astrocytes (NTAs).ConclusionsThese pilot studies of GBM patients with sodium channel mutations indicate an association with a more aggressive disease and significantly shorter survival. Moreover, inhibition of GBM cells by ion channel inhibitors such as cardiac glycosides suggest a therapeutic strategy with relatively safe drugs for targeting GBM ion channel mutations. Key Words: glioblastoma multiforme, ion channels, mutations, small molecule inhibitors, cardiac glycosides.

Highlights

Glioblastoma Multiforme (GBM) is the most common and invasive astrocytic tumor associated with dismal prognosis
Mutations in Sodium Ion Channels are Associated with Shorter Survival in GBM Patients Systematic analyses of functional gene groups and pathways from a previous study [3] identified ion channel genes that transport sodium, potassium or calcium ions as one of the gene groups most frequently mutated in GBM
The sodium, potassium and calcium ion transport gene groups were each evaluated to determine if mutations in these gene groups altered average patient survival

Summary

Introduction

Glioblastoma Multiforme (GBM) is the most common and invasive astrocytic tumor associated with dismal prognosis. Glioblastoma multiforme (GBM) is a malignant astrocytic brain tumor with a current median survival of about 15 months [1]. The survival gains for GBM patients show that progress can be made, but this progress has been slow It is not clear if large survival gains can be Recently, GBMs have undergone a large-scale mutation screen [3] and the molecular targets for this cancer can be re-evaluated. Critical to this approach is the identification of altered proteins or pathways that initiate and/or promote tumor growth. Molecular targeting efforts in GBM so far have not been translated into clinical success, despite some promising results of targeted therapy in a few other cancers

Objectives

Methods

Results

Conclusion