Prognostic relevance of epilepsy at presentation in glioblastoma patients

Berendsen, Sharon; Varkila, Meri R. J.; Kroonen, Jérôme; Seute, Tatjana; Snijders, Tom J.; Kauw, Frans; Spliet, Wim G.M.; Willems, Marie; Poulet, Christophe; Broekman, Marike L D; Bours, Vincent; Robe, Pierre A.

doi:10.1093/neuonc/nov238

Cited by 85 publications

(87 citation statements)

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“…Formalinfixed, paraffin-embedded tumor tissues of a consecutive series of GBMs operated at the University Hospital Center of Liège and from the 27 tumor UMCU samples described above were processed and included in tissue microarrays (TMAs). Details on TMA construction and immunohistochemistry have been described previously (15). A primary antibody to CK2α (Santa Cruz) was used for the immunostaining, as described previously (16) and revealed using secondary antibodies and diaminobenzidine (DAB).…”

Section: Methodsmentioning

confidence: 99%

Constitutive activation of casein kinase 2 in glioblastomas: Absence of class restriction and broad therapeutic potential

Dubois

Willems

Nguyen-Khac

et al. 2016

International Journal of Oncology

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Abstract. Casein kinase II contributes to the growth and survival of malignant gliomas and attracts increasing attention as a therapeutic target in these tumors. Several reports have suggested that this strategy might be most relevant for specific subgroups of patients, namely Verhaak's classical and TP53 wild-type tumors. Using kinase assays and microarray genetic profiling in a series of 27 proprietary fresh frozen surgical glioma samples, we showed that constitutive CK2 kinase activation is not restricted to tumors that present increased copy numbers or mRNA expression of its catalytic or regulatory subunits, and can result from a functional activation by various cytokines from the glioma microenvironment. Using corresponding primary tumor and human astrocyte cell cultures as well as glioma cell lines, we confirmed that CK2 inhibition is selectively toxic to malignant glial tumors, without any restriction to tumor class or to TP53 status. We finally showed that while the contribution of CK2 to the constitutive NF-κB hyperactivation in malignant gliomas is at best moderate, a delayed activation of NF-κB may associate with the therapeutic resistance of glioma cells to CK2 inhibition. IntroductionGlioblastomas (GBMs) are the most aggressive and prevalent type of primary brain tumors and present a dismal prognosis with a median survival of less than two years (1).Casein kinase 2 is a ubiquitous serine/threonine tetrameric kinase that consists of two catalytic subunits (α and α') and two β regulatory subunits. CK2 is frequently overexpressed or overactive in aggressive forms of solid and hematological malignancies (2,3), and contributes to the dysregulation of cell growth, invasion, survival and senescence via the β-catenin, JAK/STAT, mTOR, and NF-κB pathways (4-9). As a result, CK2 inhibitors have recently entered preliminary clinical trials for advanced solid and hematological tumors (source: ClinicalTrial.gov, accessed in December 2015).In GBMs, CSNK2A1, the gene encoding the α catalytic subunit of the kinase, is amplified in one third of the tumors, and especially in those that belong to the Verhaak's 'classical' gene expression phenotype (10). CK2 has been reported to regulate tumor-initiating cell growth, tumor cell survival, DNA repair following ionizing radiation, and apoptosis in these tumors (4,5,7,8,(11)(12)(13). As a result, CK2 inhibition with drug inhibitors or siRNA technology was shown to alter the growth, survival and migration of glioma cell lines and slow down the growth of GBMs xenografts in immunodeficient mice (9,14).Prior to translating these findings to the bedside however, it remains unclear whether CK2 hyperactivity is restricted to classical GBMs presenting a CSNK2A1 amplification or not and/or whether all malignant glial tumors are evenly likely to benefit from CK2 inhibitory strategies.This report provides evidence that CK2 kinase hyperactivity occurs in vivo in all classes of GBMs as well as in glial tumors of lower grades and histology, and can be a target independently of Verhaak's ...

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Section: Methodsmentioning

confidence: 99%

Constitutive activation of casein kinase 2 in glioblastomas: Absence of class restriction and broad therapeutic potential

Dubois

Willems

Nguyen-Khac

et al. 2016

International Journal of Oncology

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“…There are several studies on the impact of different AEDs on GBM survival [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. Previous research reports that valproate use improves survival in GBM patients [11,12,[17][18][19].…”

Section: Statistical Analysesmentioning

confidence: 99%

Does the choice of antiepileptic drug affect survival in glioblastoma patients?

et al. 2016

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Patients with glioblastoma (GBM) often suffer from symptomatic epilepsy. Older antiepileptic drugs (AEDs) which affect the enzyme system cytochrome P450 have been in extensive use, but there is an increasing focus on interactions with other drugs. This study investigated whether newer AEDs with little or no enzyme effect are increasingly preferred. Previous research has indicated that valproate improves survival in GBM. We investigated the impact of AEDs on overall survival in GBM patients. All GBM patients diagnosed in Norway 2004-2010 were included through a linkage of national registries, and follow-up data on the malignancy and drug usage were analyzed. In a multivariate cox proportional-hazards regression, AEDs were adjusted for each other and for relevant factors. Immortal time bias was eliminated with time-dependent variables. The study population was 1263 patients with histologically confirmed GBM. Carbamazepine was the most frequently prescribed AED to patients diagnosed with GBM during 2004-2006, while levetiracetam was increasingly prescribed to patients diagnosed later. Taking AEDs on a reimbursement code of epilepsy was not beneficial for survival. None of the six AEDs valproate, levetiracetam, carbamazepine, oxcarbazepine, lamotrigine or phenytoin significantly altered overall survival. There has been a shift in the prescriptions of AEDs to GBM patients from older to newer AEDs over time. We found no significant survival benefit in GBM patients neither from treatment with AEDs for epilepsy in general, nor from the usage of six separate AEDs.

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“…A further multivariate analysis of 647 patients with de novo glioblastoma identified epilepsy as a prognostic factor for longer survival. Epileptogenic tumors exhibited significantly smaller volumes than those of non-epileptogenic ones probably due to earlier detection [33]. Nevertheless, epilepsy cannot be attributed solely to early diagnosis since it was associated with better prognosis independently of tumor volume in multivariate analysis.…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, epilepsy cannot be attributed solely to early diagnosis since it was associated with better prognosis independently of tumor volume in multivariate analysis. In glioblastoma patients presenting with epilepsy, however, VPA treatment did not associate with survival [33] again challenging the value of VPA in anti-glioblastoma therapy. The conclusiveness of these studies is debated since they are retrospective in nature with limited correction for confounders, and the dosages and duration of VPA treatment were often not defined [34].…”

Section: Introductionmentioning

confidence: 99%

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Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma

Eckert

Klumpp

Huber

2017

Cell Physiol Biochem

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Background/Aims: Valproic acid (VPA), an anticonvulsant and mood-stabilizing drug is used to treat epileptic seizure of glioblastoma patients. Besides its antiepileptic activity, VPA has been attributed further functions that improve the clinical outcome of glioblastoma patients. Those comprise the inhibition of some histone deacetylase (HDAC) isoforms which reportedly may result in radiosensitization. Retrospective analysis of patient data, however, could not unequivocally confirm a prolonged survival of glioblastoma patients receiving VPA. The present study aimed to identify potential VPA targets at the cellular level. Methods: To this end, the effect of VPA on metabolism, Ca²⁺-, biochemical and electro-signaling, cell-cycling, clonogenic survival and transfilter migration was analyzed in three human glioblastoma lines (T98G, U-87MG, U251) by MTT assay, Ca²⁺ imaging, immunoblotting, patch-clamp recording, flow cytometry, delayed plating colony formation and modified Boyden chamber assays, respectively. In addition, the effect of VPA on clonogenic survival of primary glioblastoma spheroid cultures treated with temozolomide and fractionated radiation was assessed by limited dilution assay. Results: In 2 of 3 glioblastoma lines, clinical relevant concentrations of VPA slightly slowed down cell cycle progression and decreased clonogenic survival. Furthermore, VPA induced Ca²⁺ signaling which was accompanied by pronounced K⁺ channel activity and transfilter cell migration. VPA did not affect metabolic NAD(P)H formation or radioresistance of the glioblastoma lines. Finally, VPA did not impair clonogenic survival or radioresistance of temozolomide-treated primary spheroid cultures. Conclusions: Combined, our in vitro data do not propose a general use of VPA as a radiosensitizer in anti-glioblastoma therapy.

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Prognostic relevance of epilepsy at presentation in glioblastoma patients

Abstract: Epilepsy is an independent prognostic factor for longer survival in glioblastoma patients. This prognostic effect is not solely explained by early diagnosis, and survival is not associated with VPA treatment.

Cited by 85 publications

References 30 publications

Constitutive activation of casein kinase 2 in glioblastomas: Absence of class restriction and broad therapeutic potential

Constitutive activation of casein kinase 2 in glioblastomas: Absence of class restriction and broad therapeutic potential

Does the choice of antiepileptic drug affect survival in glioblastoma patients?

Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma

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