Sharon Berendsen

Valproic acid for the treatment of malignant gliomas: review of the preclinical rationale and published clinical results.

Introduction: Glioblastoma multiforme is the most common and aggressive primary brain tumor. Valproate has been used as an anti-epileptic drug and mood stabilizer for decades. Recently, it was found to inhibit the proliferation of various cancers including glioblastoma multiforme. Areas covered: We provide a comprehensive review of the mechanisms of action of valproate in gliomas, of its potential side effects and of the published clinical results obtained with this drug in glioblastomas. Valproate inhibits a subset of histone deacetylases and cellular kinases, and affects gene transcription through histone hyperacetylation, DNA hypomethylation and the modulation of several transcription factors. As a result, VPA induces differentiation of glioma cells, can prevent their invasion in surrounding tissues and may inhibit tumor angiogenesis. VPA can also inhibit DNA repair, thereby potentiating cytotoxic treatments such as chemotherapies or radiation therapy. Based on these mechanisms and case reports of glioblastoma remissions following VPA treatment, several clinical studies currently assess the therapeutic potential of VPA in glioma therapy. Expert opinion: The combination of VPA treatment with chemotherapy and radiotherapy in glioblastoma appears a rational option that deserves well-designed prospective clinical trials that assess the efficacy and the molecular characteristics of the responding tumors in these patients.

Prognostic relevance of epilepsy at presentation in glioblastoma patients.

BACKGROUND Epileptogenic glioblastomas are thought to convey a favorable prognosis, either due to early diagnosis or potential antitumor effects of antiepileptic drugs. We investigated the relationship between survival and epilepsy at presentation, early diagnosis, and antiepileptic drug therapy in glioblastoma patients. METHODS Multivariable Cox regression was applied to survival data of 647 consecutive patients diagnosed with de novo glioblastoma between 2005 and 2013 in order to investigate the association between epilepsy and survival in glioblastoma patients. In addition, we quantified the association between survival and valproic acid (VPA) treatment. RESULTS Epilepsy correlated positively with survival (HR: 0.75 (95% CI: 0.61-0.92), P < .01). This effect is independent of age, sex, performance status, type of surgery, adjuvant therapy, tumor location, and tumor volume, suggesting that this positive correlation cannot be attributed solely to early diagnosis. For patients who presented with epilepsy, the use of the antiepileptic drug VPA did not associate with survival when compared with patients who did not receive VPA treatment. CONCLUSION 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.

CXCL12 mediates glioblastoma resistance to radiotherapy in the subventricular zone

Background. Patients with glioblastoma (GBM) have an overall median survival of 15 months despite multimodal therapy. These catastrophic survival rates are to be correlated to systematic relapses that might arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. In this line, it has recently been demonstrated that GSCs are able to escape the tumor mass and preferentially colonize the adult subventricular zone (SVZ). At a distance from the initial tumor site, these GSCs might therefore represent a high-quality model of clinical resilience to therapy and cancer relapses as they specifically retain tumor-initiating abilities. Method. While relying on recent findings that have validated the existence of GSCs in the human SVZ, we questioned the role of the SVZ niche as a potential GSC reservoir involved in therapeutic failure. Results. Our results demonstrate that (i) GSCs located in the SVZ are specifically resistant to radiation in vivo, (ii) these cells display enhanced mesenchymal roots that are known to be associated with cancer radioresistance, (iii) these mesenchymal traits are specifically upregulated by CXCL12 (stromal cell-derived factor-1) both in vitro and in the SVZ environment, (iv) the amount of SVZ-released CXCL12 mediates GBM resistance to radiation in vitro, and (v) interferes with the CXCL12/CXCR4 signalling system, allowing weakening of the tumor mesenchymal roots and radiosensitizing SVZ-nested GBM cells. Conclusion. Together, these data provide evidence on how the adult SVZ environment, through the release of CXCL12, supports GBM therapeutic failure and potential tumor relapse.

I-Kappa-B Kinase-epsilon activates nuclear factor-kappa B and STAT5B and supports glioblastoma growth but amlexanox shows little therapeutic potential in these tumors

Aim: This study aims to analyze the role of I-kappa-B kinase (IKK)-epsilon in glioblastoma (GBM). Methods: A series of in vitro, in vivo, microarray, and immunohistochemical assessments were performed to evaluate the biological effects of IKK-epsilon on cell signaling, radiation sensitivity, and patient survival in GBM condition. Results: IKK-epsilon was strongly expressed in 75% of 195 primary GBM samples but did not correlate with patient survival. No correlation was established between the copy number, messenger RNA (mRNA) expression, and protein expression in 38 fresh tumor samples, nor between IKK-epsilon mRNA expression and survival in 543 GBM of the TCGA repository. In vitro, IKK-epsilon contributed to the growth and migration of glioma cells, independent of their EGFRVIII status. IKK-epsilon activated nuclear factor (NF)-κB and STAT5B in vitro, confirming the observed correlation surgical GBM samples. IKK-epsilon silencing did not alter the sensitivity of GBM cells to ionizing radiation. Amlexanox, inhibitor of IKK-epsilon and TBK1, poorly (IC50 > 100 μM) decreased cell growth and increased NF-κB activity in GBM cells, in vitro, notably due to TBK1 inhibition. In vivo, oral amlexanox failed to inhibit the growth of intracerebral U87 GBM xenografts in nude mice. Conclusion: The results confirm a moderate pro-oncogenic role of IKK-epsilon in GBM, but question the potential of amlexanox as a therapeutic drug.

Glioma-associated epilepsy: toward mechanism-based treatment

Epilepsy is common in glioma patients, and glioma-related epilepsy has a strong impact on patients’ quality of life. Glioma-related epilepsy has a unfavorable clinical course when compared to other types of symptomatic epilepsy, with low rates of seizure freedom, common relapses of seizures after seizure-free periods, and a severe outcome in case of intractable seizures (status epilepticus). Translational research is starting to elucidate the specific pathophysiological mechanisms in this disease: the molecular-biological characteristics of the tumor result in metabolic changes in the glioma and the peritumoral region. These changes lead to abnormal neuronal and non-neuronal signaling changes in the tumor’s surroundings and in the brain’s global functional network (“connectome”). Anti-neoplastic treatments often cause amelioration of epilepsy, possibly by reverting the pathophysiological pro-epileptogenic processes in the tumor. Further research should focus on these pathophysiological mechanisms and on the possibilities for new mechanism-based anti-epileptic treatments. Clinical trials for gliomas should incorporated epilepsy as an outcome measure.

214 Fractal Structure in Volumetric Contrast Enhancement of Malignant Gliomas Correlates With Oxidative Metabolic Pathway Gene Expression.

INTRODUCTION Fractal structure is found throughout many processes in nature, and often arises from sets of simple rules. We examined the contrast enhancement pattern in glioblastoma brain tumor MRIs for evidence of fractal structure, which might then be compared with expression of specific gene sets obtained from surgical specimens of each tumor. METHODS Volumetric T1 postcontrast imaging was obtained in 39 patients prior to surgical resection of pathology-confirmed glioblastoma lesions. For each tumor, we calculated the fractal dimension (Minkowski Bouligand dimension) using a box-counting (cubic scaling) approach. RNA expression microarray data from resected tissue were explored by gene set enrichment analysis (GSEA). RESULTS We found robust evidence for fractal structure in the contrast enhancement pattern, with an average fractal dimension of 2.17 ± 0.10, with a visually apparent split at 2.10. GSEA analysis showed a definitive association between this split in fractal dimension and 6 gene sets (of 4080), all 6 of which are linked to mitochondrial respiration/ATP production pathways. CONCLUSION There is fractal structure in the volumetric enhancement pattern of glioblastoma tumors, with dimension approximately 2.15. Variation in this fractal dimension, and therefore the complexity of contrast enhancement it reflects, is specifically associated with genetic correlates of a shift to glycolytic metabolism in tumor cells. Drugs that shift glioblastoma to oxidative metabolism have recently been identified as independent therapeutic agents as well as sensitizing agents for irradiation. Therefore, a radiogenomic marker of glucose metabolism, such as this fractal structure in enhancement, might help to guide individualized therapy.