End-binding 1 protein overexpression correlates with glioblastoma progression and sensitizes to <i>Vinca</i>-alkaloids <i>in vitro</i> and <i>in vivo</i>

International audienceEnd-binding 1 protein (EB1) is a key player in the regulation of microtubule (MT) dynamics. Here, we investigated the role of EB1 in glioblastoma (GBM) tumor progression and its potential predictive role for response to Vinca-alkaloid chemotherapy. Immunohistological analysis of the 109 human GBM cases revealed that EB1 overexpression correlated with poor outcome including progression-free survival and overall survival. Downregulation of EB1 by shRNA inhibited cell migration and proliferation in vitro. Conversely, EB1 overexpression promoted them and accelerated tumor growth in orthotopically-transplanted nude mice. Furthermore, EB1 was largely overexpressed in stem-like GBM6 that display in vivo a higher tumorigenicity with a more infiltrative pattern of migration than stem-like GBM9. GBM6 showed strong and EB1-dependent migratory potential. The predictive role of EB1 in the response of GBM cells to chemotherapy was investigated. Vinflunine and vincristine increased survival of EB1-overexpressing U87 bearing mice and were more effective to inhibit cell migration and proliferation in EB1-overexpressing clones than in controls. Vinca inhibited the increase of MT growth rate and growth length induced by EB1 overexpression. Altogether, our results show that EB1 expression level has a prognostic value in GBM, and that Vinca-alkaloid chemotherapy could improve the treatment of GBM patients with EB1-overexpressing tumor

Diagnosis and Treatment of Pineal Region Tumors in Adults: A EURACAN Overview

Pineal region tumors are rare intracranial tumors, accounting for less than 1% of all adult intracranial tumor lesions. These lesions represent a histologically heterogeneous group of tumors. Among these tumors, pineal parenchymal tumors and germ cell tumors (GCT) represent the most frequent types of lesions. According to the new WHO 2021 classification, pineal parenchymal tumors include five distinct histotypes: pineocytoma (PC), pineal parenchymal tumors of intermediate differentiation (PPTID), papillary tumor of the pineal region (PTPR), pinealoblastoma (PB), and desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant; GCTs include germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, mixed GCTs. Neuroradiological assessment has a pivotal role in the diagnostic work-up, surgical planning, and follow-up of patients with pineal masses. Surgery can represent the mainstay of treatment, ranging from biopsy to gross total resection, yet pineal region tumors associated with obstructive hydrocephalus may be surgically managed via ventricular internal shunt or endoscopic third ventriculostomy. Radiotherapy remains an essential component of the multidisciplinary treatment approach for most pineal region tumors; however, treatment volumes depend on the histological subtypes, grading, extent of disease, and the combination with chemotherapy. For localized germinoma, the current standard of care is chemotherapy followed by reduced-dose whole ventricular irradiation plus a boost to the primary tumor. For pinealoblastoma patients, postoperative radiation has been associated with higher overall survival. For the other pineal tumors, the role of radiotherapy remains poorly studied and it is usually reserved for aggressive (grade 3) or recurrent tumors. The use of systemic treatments mainly depends on histology and prognostic factors such as residual disease and metastases. For pinealoblastoma patients, chemotherapy protocols are based on various alkylating or platinum-based agents, vincristine, etoposide, cyclophosphamide and are used in association with radiotherapy. About GCTs, their chemosensitivity is well known and is based on cisplatin or carboplatin and may include etoposide, cyclophosphamide, or ifosfamide prior to irradiation. Similar regimens containing platinum derivatives are also used for non-germinomatous GCTs with very encouraging results. However, due to a greater understanding of the biology of the disease's various molecular subtypes, new agents based on targeted therapy are expected in the future. On behalf of the EURACAN domain 10 group, we reviewed the most important and recent developments in histopathological characteristics, neuro-radiological assessments, and treatments for pineal region tumors

Biomarqueurs prédictifs de l'activité du bevacizumab chez des patients porteurs de gliomes de haut grade à la récidive

Proposée pour un prix de thèseINTRODUCTION : l'absence de biomarqueur prédictif de l'activité des traitements anti-angiogéniques, tel le bevacizumab, reste une problématique importante en oncologie. OBJECTIF : Évaluer la valeur prédictive de biomarqueurs plasmatiques, impliqués dans la néoangiogénèse et l'invasivité, chez des patients porteurs de gliomes de haut grade traités par bevacizumab. METHODES : onze biomarqueurs plasmatiques (VEGF, VEGF2, bFGF, CXCL12, PIGF, uPA, PAI&, MMP2, MMP7, MMP9 et andrenomedulline) ont été analysés par ELISA dans une première cohorte prospective de 26 patients, lors de l'initiation du traitement de deux semaines après la première administration de bevacizumab (cohorte 1). Les résultats mis en évidence ont été validés dans une seconde cohorte indépendante (cohorte 2, n=50) et testés dans une troisième cohorte de patients n'ayant jamais reçu de bevacizumab (cohorte 3, n=34). Les dosages été corrélés aux taux de réponse objectif (OR), à la survie sans progression (PFS) et à la survie globale (OS). RESULTATS : dans la cohorte 1, un taux élevé de MMP2 à l'initiation du traitement était associé à ne probabilité de réponse de 83,3 % versus 15,4 % en cas de taux inférieur à la médiane (p=0,001). En analyse multivariée, le taux plasmatique de MMP2 était corrélé à la PFS (HR : 3,92 ; 95%IC : 1,46-10,52 ; p=0,007) et à la survie globale (HR : 4,92 ; 95%IC : 1,58-13,53 ; p=0,005), ainsi que le taux initial de MMP9 (p=0,016 for PFS ans p=0,025 for OS) et un taux décroissant de VEGF entre J1 et J15 (p=0,038 for PFS ans p=0,013 for OS). Dans la cohorte 2, MMP2, contrairement à MMP9, a confirmé sa valeur prédictive pour le taux de réponse (p<0,001), la PFS (p=0,009) et l'OS (p=0,009). Dans la cohorte 3, aucune association entre le taux de MMP2, de MMP9 et la survie n'a été retrouvée. CONCLUSION : pour les patients porteurs de gliomes de haut grade traités par bevacizumab, mais non par agent cytotoxique, un taux plasmatique élevé de MMP2 est associé à un contrôle tumoral et une survie prolongée. MMP2 devrait être analysé dans le cadre des essais prospectifs actuels et son rôle biologique réévalué

glioblastoma and angiogenesis : evolutive profile, interaction with invasiveness and therapeutic implications

Les glioblastomes sont les tumeurs primitives cérébrales les plus agressives de l’adulte. Elles sont caractérisées par une importante néo-angiogenèse, conduisant au développement des anti-VEGF chez ces patients. L’objectif de cette thèse était d’identifier de potentiels marqueurs prédictifs de l’activité du bevacizumab et d’analyser le profil évolutif des facteurs de l’angiogenèse. En situation de récidive d’un gliome de haut grade, si aucun facteur clinique ne semble permettre d’identifier un sous-groupe de patients bénéficiant particulièrement du bevacizumab, les taux plasmatiques avant traitement de MMP2 et MMP9, inversement corrélés entre eux suggérant un rôle biologique distinct mais relié, semblent associés à la réponse, la survie sans progression et la survie globale de patients porteurs de gliome de haut grade traités à la récidive par bevacizumab. Le rôle potentiel de ces marqueurs est renforcé par la cinétique de leurs taux plasmatiques observé sous traitement, Nous avons mis en évidence des résultats superposables chez des patientes porteuses de cancers du sein inflammatoires traités par bevacizumab en situation néo-adjuvante, renforçant l’intérêt de ces marqueurs. Par ailleurs, l’analyse de la signature angiogénique tissulaire des glioblastomes nouvellement diagnostiqués et récidivants nous a permis d’observer une modification de l’expression des facteurs de l’angiogenèse avec un possible switch de la voie VEGFR2-HIF1α en faveur de la voie CXCL12-CXCR4 à la récidive. Ces différents résultats permettent d’ouvrir de nouvelles perspectives dans le ciblage de l’angiogenèse et dans l’approche thérapeutique de patients porteurs de gliome de haut grade.Glioblastomas are the most frequent and aggressive primary brain tumors for adult. They are characterized by a high angiogenesis leading to the evaluation of the bevacizumab. Our aim was to identify potential predictive biomarkers of bevacizumab activity and to analyze the evolutive profile of the angiogenic factors during the disease. If no clinical factor allows the identification of patient subgroup benefiting of bevacizumab, MMP2 and MMP9 plasma level at baseline were correlated to response, progression-free survival and overall survival of patients with recurrent high grade glioma treated by bevacizumab. Moreover, plasma levels of these markers change during treatment and significantly varied at the time of progression. We observed similar results for patients with inflammatory breast cancer treated with neoadjuvant bevacizumab, reinforcing the potential value of these prebiomarkers. In tumor tissue, while we did not observed changes in MMP2/MMP9 expression between the initial diagnosis and the recurrence post radio-chemotherapy, we observed a modification of the expression of angiogenic factors with a potential switch from the VEGFR2-HIF1α to the CXCL12-CXCR4 pathway. These results lead to new perspectives in angiogenic modulation and glioblastoma treatment

TP5, a Peptide Inhibitor of Aberrant and Hyperactive CDK5/p25: A Novel Therapeutic Approach against Glioblastoma

We examined the efficacy of selective inhibition of cyclin-dependent kinase 5 (CDK5) in glioblastoma by TP5. We analyzed its impact in vitro on CDK5 expression and activity, cell survival, apoptosis and cell cycle. DNA damage was analyzed using the expression of &gamma;H2A.X and phosphorylated ATM. Its tolerance and efficacy were assessed on in vivo xenograft mouse models. We showed that TP5 decreased the activity but not the expression of CDK5 and p35. TP5 alone impaired cell viability and colony formation of glioblastoma cell lines and induced apoptosis. TP5 increased DNA damage by inhibiting the phosphorylation of ATM, leading to G1 arrest. Whereas CDK5 activity is increased by DNA-damaging agents such as temozolomide and irradiation, TP5 was synergistic with either temozolomide or irradiation due to an accumulation of DNA damage. Concomitant use of TP5 and either temozolomide or irradiation reduced the phosphorylation of ATM, increased DNA damage, and inhibited the G2/M arrest induced by temozolomide or irradiation. TP5 alone suppressed the tumor growth of orthotopic glioblastoma mouse model. The treatment was well tolerated. Finally, alone or in association with irradiation or temozolomide, TP5 prolonged mouse survival. TP5 alone or in association with temozolomide and radiotherapy is a promising therapeutic option for glioblastoma

Chemotherapy and targeted therapies for meningiomas: what is the evidence?

International audienc

Primary central nervous system lymphoma (PCNSL) in older patients

Introduction Primary central nervous system lymphoma (PCNSL) is a rare, chemo and radio-sensitive tumor limited to the central nervous system. The incidence of PCSNL increases notably in the elderly population which represented approximately half of the patients. The limit of ‘elderly’ population remained debated and nonuniform, including 60 years as a cutoff for brain radiotherapy, 65 years for autologous stem-cell transplantation, and 70 years for the last clinical trials. Current therapeutic options include first line treatment based on high-dose methotrexate based polychemotherapy, consolidation chemotherapy, and adapted autologous stem cell transplantation for highly selected patients. At relapse, single agent targeted therapies or salvage chemotherapy followed by intensive consolidation are promising therapeutic options. Nevertheless, improving management of elderly patients is an urgent medical need that currently remains unresolved. Objective We will focus on elderly patients with PCNSL and their specificities including clinical presentations, available therapeutic options and adaptations to be made. Conclusion To improve survival, it will be necessary to personalized and adapt the treatments, to each patient and his comorbidities, to increase their effectiveness and limit their toxicity in this frail population. Finally, inclusion of these patients in clinical trials is one of the major challenges to significantly change PCNSL elderly patient prognosis

Editorial: Novel diagnostic and therapeutic strategies in the management of cerebral gliomas

Editorial on the Research Topic Novel diagnostic and therapeutic strategies in the management of cerebral gliomas Frontiers in Oncology frontiersin.org 0

Predictive value of lymphocyte immunophenotyping (LIP) in primary central nervous system lymphoma (PCNSL).

International audience2063 Background: Immunity plays an important role in PCNSL development. PCNSL predictive factors need to be improved. Objective: to evaluate the characteristics and predictive value of blood LIP in PCNSL patients. Methods: we prospectively analyzed blood LIP in all newly PCNSL referred to our institution between December 2013 and January 2020. LIP analysis was performed before rituximab and chemotherapy administration. The clinical, radiological, histological, biological and treatment data were retrospectively collected. Results: fifty-three patients were included with a median age of 69.7 (range 21.7-87.5). Median KPS was 60 (range 30-100). All patients presented with cerebral involvement, 13 (25%) with cerebrospinal fluid extension and 8 (15%) with ocular extension. Thirty-four patients (62%) benefited of steroid treatment at the time of LIP. Patients characteristics did not differ depending on steroid intake. Forty-eight patients (95%) benefited of polychemotherapy with high-dose methotrexate as first line treatment. We observed three (6%) lymphoproliferative syndromes on the LIP and 33 patients (64%) presented with one or several lymphopenias: 21 (40%), 24 (46%) and 9 (17%) NK, T and B lymphopenias respectively. Only 11 patients (21%) had normal LIP. Median CD4/CD8 ratio was 2.11 (range 0.54-9.11). This ratio was normal, low or high in 27%, 28% and 44% of patients respectively. The presence of steroids did not impact LIP results, including CD4 (p = 0.475) or CD8 (p = 0.726) rates and CD4/CD8 ratio (p = 0.727). Complete or partial responses, stable and progressive disease (PD) were observed in 24 (50%), 10 (21%), 4 (8%), and 10 (21%) patients respectively. CD4/CD8 ratio tended to be different between refractory (PD patients) and non-refractory patients (p = 0.077). A ROC curve analysis was performed with an AUC of 0.684 allowing the selection of a CD4/CD8 ratio cutoff of 1.97 with a sensibility, specificity, positive predictive value, and negative predictive value to identify refractory patients of 90%, 55%, 35% and 95% respectively. Median progression-free survival (PFS) and overall survival (OS) were 14.7 (95%CI: 6.5-22.9) and 43.2 (95%CI: 21.6-64.9) months, respectively. In multivariate analyses, adjusted by KPS, a CD4/CD8 ratio > 1.97 was associated with poor PFS (p = 0.043, HR = 3.32 [1.02-4.88]) and tended to be associated with worse OS (p = 0.064). Conclusions: LIP at baseline may predict refractory disease and exhibits a prognostic value in PCNSL patients