Pierre-Jean Le Reste

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

Combined therapies targeting the unfolded protein stress response might be a way to treat glioblastomas. Gloss Glioblastoma (GBM) is the most common and aggressive brain tumor. Standard care combines surgery, radiotherapy, and chemotherapy, but patient median survival does not exceed 15 months. The unfolded protein response (UPR) is an adaptive cellular signaling pathway that promotes restoration of endoplasmic reticulum proteostasis. The UPR plays instrumental roles in various cancers, particularly growth, invasion, therapeutic resistance, and angiogenesis in GBM. In this Review, which contains four figures, two tables, and 219 references, we discuss how adjuvant or neoadjuvant UPR-targeted compounds could impede GBM growth and increase the efficacy of current treatments. Cellular stress induced by the accumulation of misfolded proteins at the endoplasmic reticulum (ER) is a central feature of secretory cells and is observed in many tissues in various diseases, including cancer, diabetes, obesity, and neurodegenerative disorders. Cellular adaptation to ER stress is achieved by the activation of the unfolded protein response (UPR), an integrated signal transduction pathway that transmits information about the protein folding status at the ER to the cytosol and nucleus to restore proteostasis. In the past decade, ER stress has emerged as a major pathway in remodeling gene expression programs that either prevent transformation or provide selective advantage in cancer cells. Controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, UPR signaling is a highly regulated process that leads to an integrated reprogramming of the cell. In this Review, we provide an overview of the regulatory mechanisms underlying UPR signaling and how this pathway modulates cancer progression, particularly the aggressiveness and chemotherapeutic resistance exhibited by glioblastoma, a form of brain cancer. We also discuss the emerging cross-talk between the UPR and related metabolic processes to ensure maintenance of proteostasis, and we highlight possible therapeutic opportunities for targeting the pathway with small molecules.

Dual IRE1 RNase functions dictate glioblastoma development

Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Evidence suggests that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept is valid in glioblastoma multiform (GBM), the most lethal primary brain cancer with no effective treatment. We previously demonstrated that the ER stress sensor IRE1α (referred to as IRE1) contributes to GBM progression, through XBP1 mRNA splicing and regulated IRE1‐dependent decay (RIDD) of RNA. Here, we first demonstrated IRE1 signaling significance to human GBM and defined specific IRE1‐dependent gene expression signatures that were confronted to human GBM transcriptomes. This approach allowed us to demonstrate the antagonistic roles of XBP1 mRNA splicing and RIDD on tumor outcomes, mainly through selective remodeling of the tumor stroma. This study provides the first demonstration of a dual role of IRE1 downstream signaling in cancer and opens a new therapeutic window to abrogate tumor progression.

Delaying standard combined chemoradiotherapy after surgical resection does not impact survival in newly diagnosed glioblastoma patients.

BACKGROUND To assess the influence of the time interval between surgical resection and standard combined chemoradiotherapy on survival in newly diagnosed and homogeneously treated (surgical resection plus standard combined chemoradiotherapy) glioblastoma patients; while controlling confounding factors (extent of resection, carmustine wafer implantation, functional status, neurological deficit, and postoperative complications). METHODS From 2005 to 2011, 692 adult patients (434 men; mean of 57.5 ± 10.8 years) with a newly diagnosed glioblastoma were enrolled in this retrospective multicentric study. All patients were treated by surgical resection (65.5% total/subtotal resection, 34.5% partial resection; 36.7% carmustine wafer implantation) followed by standard combined chemoradiotherapy (radiotherapy at a median dose of 60 Gy, with daily concomitant and adjuvant temozolomide). Time interval to standard combined chemoradiotherapy was analyzed as a continuous variable and as a dichotomized variable using median and quartiles thresholds. Multivariate analyses using Cox modeling were conducted. RESULTS The median progression-free survival was 10.3 months (95% CI, 10.0-11.0). The median overall survival was 19.7 months (95% CI, 18.5-21.0). The median time to initiation of combined chemoradiotherapy was 1.5 months (25% quartile, 1.0; 75% quartile, 2.2; range, 0.1-9.0). On univariate and multivariate analyses, OS and PFS were not significantly influenced by time intervals to adjuvant treatments. On multivariate analysis, female gender, total/subtotal resection and RTOG-RPA classes 3 and 4 were significant independent predictors of improved OS. CONCLUSIONS Delaying standard combined chemoradiotherapy following surgical resection of newly diagnosed glioblastoma in adult patients does not impact survival.

Influence of cumulative surgical experience on the outcome of poor-grade patients with ruptured intracranial aneurysm

BackgroundThe expansion of endovascular techniques for intracranial aneurysms has led to a global decrease in vascular neurosurgery activity. This situation might impact neurosurgeons’ level of expertise, even though they all might have to deal with this surgically challenging pathology. In that context, we wanted to assess the impact of cumulative surgical experience on the outcome of patients with poor-grade subarachnoid haemorrhage (SAH) and intracerebral haemorrhage (ICH) treated by microsurgery.MethodsSixty-seven patients who underwent surgery for a ruptured aneurysm with SAH and ICH, and a WFNS scale of IV/V, were included. Surgeries were performed by five surgeons, whose experience was judged by the total number of aneurysm surgeries performed. The outcome was assessed by three indicators: intraoperative rupture (IOR), early mortality, and the modified Rankin Scale at last follow-up. The time of IOR was reported on an IOR score. The correlation between surgical experience and outcome was assessed by linear regression. Nonlinear regression was used to assess the correlation of the data with a learning curve model.ResultsThe analysis showed an influence of surgical experience on intraoperative rupture, with no effect on long-term outcome. No influence was found on early mortality. Increased surgical experience seems to reduce IOR during aneurysm dissection and clip repositioning. Intraoperative rupture data fit Wright’s learning curve model.ConclusionThis study suggests a direct impact of cumulative experience on the course of ruptured aneurysm surgery and pleads for the use of training and simulation programmes dedicated to neurovascular surgery.

Recurrent glioblastomas in the elderly after maximal first-line treatment: does preserved overall condition warrant a maximal second-line treatment?

A growing literature supports maximal safe resection followed by standard combined chemoradiotherapy (i.e. maximal first-line therapy) for selected elderly glioblastoma patients. To assess the prognostic factors from recurrence in elderly glioblastoma patients treated by maximal safe resection followed by standard combined chemoradiotherapy as first-line therapy. Multicentric retrospective analysis comparing the prognosis and optimal oncological management of recurrent glioblastomas between 660 adult patients aged of < 70 years (standard group) and 117 patients aged of ≥70 years (elderly group) harboring a supratentorial glioblastoma treated by maximal first-line therapy. From recurrence, both groups did not significantly differ regarding Karnofsky performance status (KPS) (p = 0.482). Oncological treatments from recurrence significantly differed: patients of the elderly group received less frequently oncological treatment from recurrence (p < 0.001), including surgical resection (p < 0.001), Bevacizumab therapy (p < 0.001), and second line chemotherapy other than Temozolomide (p < 0.001). In multivariate analysis, Age ≥70 years was not an independent predictor of overall survival from recurrence (p = 0.602), RTOG-RPA classes 5–6 (p = 0.050) and KPS at recurrence <70 (p < 0.001), available in all cases, were independent significant predictors of shorter overall survival from recurrence. Initial removal of ≥ 90% of enhancing tumor (p = 0.004), initial completion of the standard combined chemoradiotherapy (p = 0.007), oncological treatment from recurrence (p < 0.001), and particularly surgical resection (p < 0.001), Temozolomide (p = 0.046), and Bevacizumab therapy (p = 0.041) were all significant independent predictors of longer overall survival from recurrence. Elderly patients had substandard care from recurrence whereas age did not impact overall survival from recurrence contrary to KPS at recurrence <70. Treatment options from recurrence should include repeat surgery, second line chemotherapy and anti-angiogenic agents.

Natural course and prognosis of anaplastic gangliogliomas: a multicenter retrospective study of 43 cases from the French Brain Tumor Database

Background Anaplastic gangliogliomas (GGGs) are rare tumors whose natural history is poorly documented. We aimed to define their clinical and imaging features and to identify prognostic factors. Methods Consecutive cases of anaplastic GGGs in adults prospectively entered into the French Brain Tumor Database between March 2004 and April 2014 were screened. After diagnosis was confirmed by pathological review, clinical, imaging, therapeutic, and outcome data were collected retrospectively. Results Forty-three patients with anaplastic GGG (median age, 49.4 y) from 18 centers were included. Presenting symptoms were neurological deficit (37.2%), epileptic seizure (37.2%), or increased intracranial pressure (25.6%). Typical imaging findings were unifocal location (94.7%), contrast enhancement (88.1%), central necrosis (43.2%), and mass effect (47.6%). Therapeutic strategy included surgical resection (95.3%), adjuvant radiochemotherapy (48.8%), or radiotherapy alone (27.9%). Median progression-free survival (PFS) and overall survival (OS) were 8.0 and 24.7 months, respectively. Three- and 5-year tumor recurrence rates were 69% and 100%, respectively. The 5-year survival rate was 24.9%. Considering unadjusted significant prognostic factors, tumor midline crossing and frontal location were associated with shorter OS. Temporal and parietal locations were associated with longer and shorter PFS, respectively. None of these factors remained statistically significant in multivariate analysis. Conclusions We report a large series providing clinical, imaging, therapeutic, and prognostic features of adult patients treated for an intracerebral anaplastic GGG. Our results show that pathological diagnosis is difficult, that survivals are only slightly better than for glioblastomas, and that complete surgical resection followed with adjuvant chemoradiotherapy offers longer survival.

Signaling the Unfolded Protein Response in primary brain cancers

The Unfolded Protein Response (UPR) is an adaptive cellular program used by eukaryotic cells to cope with protein misfolding stress in the Endoplasmic Reticulum (ER). During tumor development, cancer cells are facing intrinsic (oncogene activation) and extrinsic (limiting nutrient or oxygen supply; exposure to chemotherapies) challenges, with which they must cope to survive. Primary brain tumors are relatively rare but deadly and present a significant challenge in the determination of risk factors in the population. These tumors are inherently difficult to cure because of their protected location in the brain. As such surgery, radiation and chemotherapy options carry potentially lasting patient morbidity and incomplete tumor cure. Some of these tumors, such as glioblastoma, were reported to present features of ER stress and to depend on UPR activation to sustain growth, but to date there is no clear general representation of the ER stress status in primary brain tumors. In this review, we describe the key molecular mechanisms controlling the UPR and their implication in cancers. Then we extensively review the literature reporting the status of ER stress in various primary brain tumors and discuss the potential impact of such observation on patient stratification and on the possibility of developing appropriate targeted therapies using the UPR as therapeutic target.

Modern Management of Meningiomas Compressing the Optic Nerve: A Systematic Review

OBJECTIVE Meningiomas that compress the optic nerve (ON) can lead to different visual outcomes depending on the segment of ON affected (intraorbital, canalicular, and intracranial). In this study, we performed a comprehensive comparison of the management options (surgery, radiation, or observation alone) for meningiomas compressing the ON, categorized by location and relation to the ON. METHODS MEDLINE, EMBASE, Web of Science, and the Cochrane Database of Systematic reviews databases were searched according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Data were extracted from the articles regarding anatomic location, initial visual impairment, surgical procedure, visual outcome, morbidity and mortality, gross total removal, and requirement for postoperative radiotherapy. RESULTS Of the 47 articles eligible for full-text reading, 9 surgical studies met our inclusion criteria. Data from 317 patient cases were extracted. In patients in whom the intracranial segment of the ON was impaired in isolation, 49% experienced visual improvement after surgery. When the meningioma affected the canalicular segment or intraorbital segment, visual improvement after surgery was 31% and 11%, respectively. Of patients who underwent surgery for the intraorbital segment of the ON, 56% experienced a decline in visual outcome. CONCLUSIONS When a neurosurgeon deals with a meningioma compressing the ON, opening the optic canal is suggested if invasion is suspected on the preoperative imaging. Extra caution should be used when operating on meningiomas with ON sheath adhesion, given the higher evidence of postoperative visual worsening.

Comparison of neurogenic lower urinary tract dysfunctions in open versus closed spinal dysraphism: A prospective cross-sectional study of 318 patients

To compare the neurogenic lower urinary tract dysfunction (NLUTD) in patients with closed spinal dysraphism (CSD) versus patients with open spinal dysraphism (OSD) as well as their management patterns.

Prognostic factors for survival in adult patients with recurrent glioblastoma: a decision-tree-based model

We assessed prognostic factors in relation to OS from progression in recurrent glioblastomas. Retrospective multicentric study enrolling 407 (training set) and 370 (external validation set) adult patients with a recurrent supratentorial glioblastoma treated by surgical resection and standard combined chemoradiotherapy as first-line treatment. Four complementary multivariate prognostic models were evaluated: Cox proportional hazards regression modeling, single-tree recursive partitioning, random survival forest, conditional random forest. Median overall survival from progression was 7.6 months (mean, 10.1; range, 0–86) and 8.0 months (mean, 8.5; range, 0–56) in the training and validation sets, respectively (p = 0.900). Using the Cox model in the training set, independent predictors of poorer overall survival from progression included increasing age at histopathological diagnosis (aHR, 1.47; 95% CI [1.03–2.08]; p = 0.032), RTOG–RPA V–VI classes (aHR, 1.38; 95% CI [1.11–1.73]; p = 0.004), decreasing KPS at progression (aHR, 3.46; 95% CI [2.10–5.72]; p < 0.001), while independent predictors of longer overall survival from progression included surgical resection (aHR, 0.57; 95% CI [0.44–0.73]; p < 0.001) and chemotherapy (aHR, 0.41; 95% CI [0.31–0.55]; p < 0.001). Single-tree recursive partitioning identified KPS at progression, surgical resection at progression, chemotherapy at progression, and RTOG–RPA class at histopathological diagnosis, as main survival predictors in the training set, yielding four risk categories highly predictive of overall survival from progression both in training (p < 0.0001) and validation (p < 0.0001) sets. Both random forest approaches identified KPS at progression as the most important survival predictor. Age, KPS at progression, RTOG–RPA classes, surgical resection at progression and chemotherapy at progression are prognostic for survival in recurrent glioblastomas and should inform the treatment decisions.