Prediction of clinical outcome in glioblastoma using a biologically relevant nine-microRNA signature

Background Glioblastoma is the most aggressive primary brain tumor, and is associated with a very poor prognosis. In this study we investigated the potential of microRNA expression profiles to predict survival in this challenging disease. Methods MicroRNA and mRNA expression data from glioblastoma (n = 475) and grade II and III glioma (n = 178) were accessed from The Cancer Genome Atlas. LASSO regression models were used to identify a prognostic microRNA signature. Functionally relevant targets of microRNAs were determined using microRNA target prediction, experimental validation and correlation of microRNA and mRNA expression data. Results A 9-microRNA prognostic signature was identified which stratified patients into risk groups strongly associated with survival (p = 2.26e−09), significant in all glioblastoma subtypes except the non-G-CIMP proneural group. The statistical significance of the microRNA signature was higher than MGMT methylation in temozolomide treated tumors. The 9-microRNA risk score was validated in an independent dataset (p = 4.50e−02) and also stratified patients into high- and low-risk groups in lower grade glioma (p = 5.20e−03). The majority of the 9 microRNAs have been previously linked to glioblastoma biology or treatment response. Integration of the expression patterns of predicted microRNA targets revealed a number of relevant microRNA/target pairs, which were validated in cell lines. Conclusions We have identified a novel, biologically relevant microRNA signature that stratifies high- and low-risk patients in glioblastoma. MicroRNA/mRNA interactions identified within the signature point to novel regulatory networks. This is the first study to formulate a survival risk score for glioblastoma which consists of microRNAs associated with glioblastoma biology and/or treatment response, indicating a functionally relevant signatur

The Hepatocyte Growth Factor (HGF)/Met Axis: A Neglected Target in the Treatment of Chronic Myeloproliferative Neoplasms?

Met is the receptor of hepatocyte growth factor (HGF), a cytoprotective cytokine. Disturbing the equilibrium between Met and its ligand may lead to inappropriate cell survival, accumulation of genetic abnormalities and eventually, malignancy. Abnormal activation of the HGF/Met axis is established in solid tumours and in chronic haematological malignancies, including myeloma, acute myeloid leukaemia, chronic myelogenous leukaemia (CML), and myeloproliferative neoplasms (MPNs). The molecular mechanisms potentially responsible for the abnormal activation of HGF/Met pathways are described and discussed. Importantly, inCML and in MPNs, the production of HGF is independent of Bcr-Abl and JAK2V617F, the main molecular markers of these diseases. In vitro studies showed that blocking HGF/Met function with neutralizing antibodies or Met inhibitors significantly impairs the growth of JAK2V617F-mutated cells. With personalised medicine and curative treatment in view, blocking activation of HGF/Met could be a useful addition in the treatment of CML and MPNs for those patients with high HGF/MET expression not controlled by current treatments (Bcr-Abl inhibitors in CML; phlebotomy, hydroxurea, JAK inhibitors in MPNs)

Jak2, cytokines et récepteurs dans la polyglobulie de Vaquez

La polyglobulie de Vaquez (PV) appartient à la famille des syndromes myéloprolifératifs (SMP). C'est une maladie clonale dont l'origine se situe au niveau d'un progéniteur multipotent. En 2005, la description de la mutation JAK2V617F et sa présence dans 95% des cas de PV, à la fois à l état homozygote et hétérozygote, a été le point de départ de nouvelles interrogations concernant les mécanismes moléculaires impliqués dans la pathogénèse de cette maladie. L objectif de ce travail a été, dans un premier temps, de mettre au point une technique sensible de PCR quantitative spécifique d allèle. Cette technique a permis d étudier le niveau d expression de JAK2V617F chez les patients au diagnostic de SMP. Nous avons, ensuite, utilisé cette même approche pour étudier l importance de la détection de JAK2V617F pour la détection de SMP latent dans les présentations atypiques comme les thromboses digestives profondes et les anémies réfractaires sidéroblastiques. Nous avons également, en collaboration, déterminé que quand un SMP positif pour JAK2V617F se transforme en leucémie aigue myéloïde, celle-ci est fréquemment négative pour la mutation. Il a également été mis en évidence que les clones JAK2V617F positifs et négatifs peuvent se développer à partir d un ancêtre commun. Enfin, nous avons décrit dans la PV, la dérégulation de la production, au niveau protéique et ARN messager, de plusieurs cytokines hématopoïétiques et de leur voie de signalisation (IL-11, IL-6, gp130, JAK2, STAT3). Cette dérégulation participe à l'hématopoïèse anormale dans la PV. Ces mécanismes, indépendants de JAK2V617F, semblent maintenir l'équilibre entre les voies JAK2V617F/STAT5 et JAK2/STAT3.Polycythemia Vera (PV) belongs to the family of myeloproliferative disorders (MPD). It is a clonal disease arising from a multipotent progenitor. In 2005, the JAK2V617F mutation was discovered as a MPD specific mutation present in more than 95% of PV patients both at homozygous and heterozygous state. This discovery was the starting point of a new area in the understanding of molecular mechanisms invloved in MPD pathogenesis. The aim of our work was, first to set up an assay of allele specific quantitative PCR. Thanks to this assay, we were able to study the importance of JAK2V617F mutation at diagnosis of MPD. We also used this assay to investigate the relevance of JAK2V617F detection for the diagnosis of latent MPD in atypical presentations like splanchnic vein thrombosis and refractory anemia with ringed sideroblasts. In addition, in collaboration, we have determined that positive JAK2V617F MPD often transform into JAK2V617F negative acute myeloid leukemia, and that both clones may derive from the same JAK2V617F negative ancestral clone. Finally, we have described , in PV patients, elevated production of hematopoietic cytokines (IL-11, IL-6), both at the protein and messenger RNA level. Their signaling pathway (gp130, JAK2, STAT3) was also dysregulated and this pathway is involved in PV abnormal hematopoiesis. This mecHanism is independent from JAK2V617F and seems to maintain the balance between the JAK2V617F/STAT5 and JAK2/STAT3 pathways.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

The Hepatocyte Growth Factor (HGF)/Met Axis: A Neglected Target in the Treatment of Chronic Myeloproliferative Neoplasms?

Met is the receptor of hepatocyte growth factor (HGF), a cytoprotective cytokine. Disturbing the equilibrium between Met and its ligand may lead to inappropriate cell survival, accumulation of genetic abnormalities and eventually, malignancy. Abnormal activation of the HGF/Met axis is established in solid tumours and in chronic haematological malignancies, including myeloma, acute myeloid leukaemia, chronic myelogenous leukaemia (CML), and myeloproliferative neoplasms (MPNs). The molecular mechanisms potentially responsible for the abnormal activation of HGF/Met pathways are described and discussed. Importantly, inCML and in MPNs, the production of HGF is independent of Bcr-Abl and JAK2V617F, the main molecular markers of these diseases. In vitro studies showed that blocking HGF/Met function with neutralizing antibodies or Met inhibitors significantly impairs the growth of JAK2V617F-mutated cells. With personalised medicine and curative treatment in view, blocking activation of HGF/Met could be a useful addition in the treatment of CML and MPNs for those patients with high HGF/MET expression not controlled by current treatments (Bcr-Abl inhibitors in CML; phlebotomy, hydroxurea, JAK inhibitors in MPNs)

GSK-3 Inhibition Is Cytotoxic in Glioma Stem Cells through Centrosome Destabilization and Enhances the Effect of Radiotherapy in Orthotopic Models

Background: Previous data on glycogen synthase kinase 3 (GSK-3) inhibition in cancer models support a cytotoxic effect with selectivity for tumor cells compared to normal tissue but the effect of these inhibitors in glioma has not been widely studied. Here, we investigate their potential as cytotoxics in glioma. Methods: We assessed the effect of pharmacologic GSK-3 inhibition on established (U87, U251) and patient-derived (GBM1, GBM4) glioblastoma (GBM) cell lines using cytotoxicity assays as well as undertaking a detailed investigation of the effect on cell cycle, mitosis, and centrosome biology. We also assessed drug uptake and efficacy of GSK-3 inhibition alone and in combination with radiation in xenograft models. Results: Using the selective GSK-3 inhibitor AZD2858, we demonstrated single agent cytotoxicity in two patient-derived glioma cell lines (GBM1, GBM4) and two established cell lines (U251 and U87) with IC50 in the low micromolar range promoting centrosome disruption, failed mitosis, and S-phase arrest. Glioma xenografts exposed to AZD2858 also showed growth delay compared to untreated controls. Combined treatment with radiation increased the cytotoxic effect of clinical radiation doses in vitro and in orthotopic glioma xenografts. Conclusions: These data suggest that GSK-3 inhibition promotes cell death in glioma through disrupting centrosome function and promoting mitotic failure and that AZD2858 is an effective adjuvant to radiation at clinical doses