February 11, 2011Open Access
Sodium ion channel mutations in glioblastoma patients correlate with shorter survival
Resultado clave
Glioblastoma patients with sodium channel mutations had a significantly shorter median survival of 148 days compared to 689 days for patients without these mutations.
Diseño del estudio
Tipo
Observational (n=21)
PICO estructurado
Do sodium ion channel mutations correlate with survival in GBM patients, and do cardiac glycosides inhibit GBM cell proliferation?
P
Población
21 patients with Glioblastoma Multiforme (GBM) who underwent tumor sequencing, median age 45, 13 males, 8 females, with no prior chemo or radiation therapy. In vitro models included U-87 and D54 GBM cell lines and non-tumor astrocytes.
I
Intervención
Presence of somatic mutations in sodium ion channel genes (clinical cohort); treatment with cardiac glycosides (digoxin and ouabain) at 10 nM to 50 μM (in vitro).
C
Comparador
Absence of sodium ion channel mutations (clinical cohort); vehicle control and non-tumor astrocytes (in vitro).
O
Resultado
Patient survival defined as time in days from first surgical resection of GBM to death (clinical); cell proliferation and cytotoxicity at 72 hours (in vitro).hard clinical
Resultado numérico
Tasa de eventos absoluta: 148% vs 689%
valor p: p=0.0079
Limitaciones
- Small sample size (21 patients total, with survival data available for only 16)
- Potential confounding by IDH1 mutations, as all IDH1-mutated patients were in the unmutated sodium channel group
- Lack of molecular evidence explaining how these specific mutations alter the clinical course of the disease
Resumen
BACKGROUND: Glioblastoma 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. RESULTS: Nearly 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). CONCLUSIONS: These 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.