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PubMed | Biostatistics., University of Houston, Pathology, University of Lausanne and 6 more.
Type: Journal Article | Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience | Year: 2015

Glioblastoma (GBM) is the most aggressive human brain tumor. Although several molecular subtypes of GBM are recognized, a robust molecular prognostic marker has yet to be identified. Here, we report that the stemness regulator Sox2 is a new, clinically important target of microRNA-21 (miR-21) in GBM, with implications for prognosis. Using the MiR-21-Sox2 regulatory axis, approximately half of all GBM tumors present in the Cancer Genome Atlas (TCGA) and in-house patient databases can be mathematically classified into high miR-21/low Sox2 (Class A) or low miR-21/high Sox2 (Class B) subtypes. This classification reflects phenotypically and molecularly distinct characteristics and is not captured by existing classifications. Supporting the distinct nature of the subtypes, gene set enrichment analysis of the TCGA dataset predicted that Class A and Class B tumors were significantly involved in immune/inflammatory response and in chromosome organization and nervous system development, respectively. Patients with Class B tumors had longer overall survival than those with Class A tumors. Analysis of both databases indicated that the Class A/Class B classification is a better predictor of patient survival than currently used parameters. Further, manipulation of MiR-21-Sox2 levels in orthotopic mouse models supported the longer survival of the Class B subtype. The MiR-21-Sox2 association was also found in mouse neural stem cells and in the mouse brain at different developmental stages, suggesting a role in normal development. Therefore, this mechanism-based classification suggests the presence of two distinct populations of GBM patients with distinguishable phenotypic characteristics and clinical outcomes.Molecular profiling-based classification of glioblastoma (GBM) into four subtypes has substantially increased our understanding of the biology of the disease and has pointed to the heterogeneous nature of GBM. However, this classification is not mechanism based and its prognostic value is limited. Here, we identify a new mechanism in GBM (the miR-21-Sox2 axis) that can classify 50% of patients into two subtypes with distinct molecular, radiological, and pathological characteristics. Importantly, this classification can predict patient survival better than the currently used parameters. Further, analysis of the miR-21-Sox2 relationship in mouse neural stem cells and in the mouse brain at different developmental stages indicates that miR-21 and Sox2 are predominantly expressed in mutually exclusive patterns, suggesting a role in normal neural development.


PubMed | Pathology and Brain Pathology and., Aix - Marseille University, Neuro oncology and Hopital Nord
Type: | Journal: Journal of neurosurgery | Year: 2016

OBJECTIVE Meningiomas express somatostatin receptor subtype 2 (SST2), which is targeted by the somatostatin analog octreotide. However, to date, using somatostatin analog therapy for the treatment of these tumors in clinical practice has been debated. This study aims to clarify the in vitro effects of octreotide on meningiomas for precise clinical applications. METHODS The effects of octreotide were analyzed in a large series of 80 meningiomas, including 31 World Health Organization (WHO) Grade II and 4 WHO Grade III tumors, using fresh primary cell cultures to study the impact on cell viability, apoptosis, and signal transduction pathways. RESULTS SST2 mRNA was detected in 100% of the tested meningiomas at levels similar to those observed in other SST2-expressing tumors, neuroendocrine tumors, or pituitary adenomas. Octreotide significantly decreased cell proliferation in 88% of meningiomas but did not induce cell death. On average, cell proliferation was more inhibited in the meningioma group expressing a high level of SST2 than in the low-SST2 group. Moreover, octreotide response was positively correlated to the level of merlin protein and inversely correlated to the level of phosphorylated p70-S6 kinase, a downstream effector of the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway. Octreotide inhibited Akt phosphorylation and activated tyrosine phosphatase without impacting the extracellular regulated kinase (ERK) pathway. CONCLUSIONS Octreotide acts exclusively as an antiproliferative agent and does not promote apoptosis in meningioma in vitro. Therefore, in vivo, octreotide is likely to limit tumor growth rather than induce tumor shrinkage. A meta-analysis of the literature reveals an interest in octreotide for the treatment of WHO Grade I tumors, particularly those in the skull base for which the 6-month progression-free survival level reached 92%. Moreover, somatostatin analogs, which are well-tolerated drugs, could be of interest for use as co-targeting therapies for aggressive meningiomas.


Marizomib is a novel brain-penetrant proteasome inhibitor in development for patients with glioblastoma and relapsed and/or refractory multiple myeloma TORONTO and SAN DIEGO, Nov. 18, 2016 (GLOBE NEWSWIRE) -- Triphase Accelerator Corporation, a private drug development company dedicated to advancing novel compounds through clinical Phase 2 proof-of-concept, today announced positive full enrollment results from its multicenter, open label, Phase 1 study evaluating marizomib (MRZ) in combination with bevacizumab (BEV) in patients with WHO grade IV malignant glioma.  The study results were presented at the Society of Neuro Oncology meeting today in Scottsdale, Arizona.  Triphase separately announced on November 17, 2016 that Celgene acquired the assets relating to MRZ. “These results continue to demonstrate the potential benefit of both the combination therapy of MRZ and BEV, as well as MRZ monotherapy, for recurrent glioma," said Daniela Bota, M.D., medical director of Neuro-Oncology and associate professor of neurology at the University of California, Irvine, and lead investigator of the study.  “As we reported for our interim results, adding the expansion cohort of monotherapy with MRZ was extremely helpful in achieving robust results, and we think we may have established an optimal dosing regimen.” The Phase 1 open-label dose-escalation study included three dose escalation cohorts plus an expansion cohort, for a total of 36 recurrent glioma patients receiving MRZ on days 1, 8, and 15, with standard dose of bevacizumab (BEV at 10mg/kg) on days 1 and 15, of a 28-day cycle. The MRZ+BEV combination was well tolerated with no dose limiting toxicity at 0.8 mg/m2, which was the highest dose of MRZ evaluated in this study. The Response Rate (by Response Assessment in Neuro-Oncology (RANO) criteria) was 42% (14/33) in efficacy evaluable patients, with 34% of patients achieving six months progression-free survival (PFS) and 55% achieving nine months overall survival (OS).  The 6 and 9 months PFS in patients with unmethylated MGMT – a marker of poor prognosis and resistance to standard-of-care in glioblastoma - were 34% and 23%, respectively.  These data are comparable to PFS in all patients (34% PFS 6 months, 22% PFS 9 months), suggesting a potentially unique clinical benefit of MRZ+BEV in this difficult to treat segment of glioblastomas.  To date, the 9 months OS in unmethylated MGMT patients is 44%, with data collection continuing for most patients. In an ongoing Phase 2 (MRZ monotherapy) portion of the study, a total of 15 recurrent glioma patients have been enrolled to date, receiving 0.8 mg/m2 MRZ on days 1, 8, and 15 of a 28-day cycle.  MRZ monotherapy in these patients has resulted in a partial remission in 1 patient, and stable disease in 2 additional patients, demonstrating activity of MRZ as a single agent.  Based on these data, the study will continue enrollment up to 30 total patients.  MRZ is generally well tolerated in combination with BEV and as monotherapy.  The most common study treatment-related adverse events across both phases of the study include fatigue, headache, nausea, diarrhea, dysphonia, hypertension, vomiting, hallucination and weakness. “These clinical proof of concept results further support the value of MRZ as a potential treatment for recurrent glioma,” said Mohit Trikha, Ph.D., Chief Scientific Officer and head of Triphase Accelerator Research and Development.  “Equally as important for Triphase Accelerator, these results were instrumental to Celgene’s decision to acquire the compound.” About Marizomib Marizomib is a novel, brain-penetrant proteasome inhibitor, which inhibits all three proteasome subunits. Triphase Accelerator is developing marizomib in both intravenous (IV) and oral formulations as a proteasome inhibitor for hematologic malignancies and solid tumors. The IV formulation has been evaluated in more than 300 patients in multiple clinical studies in patients with solid and hematologic malignancies, either as a single agent or in combination with dexamethasone, a histone deacetylase inhibitor, or an immunomodulatory drug. The company is currently evaluating marizomib in a proof-of-concept clinical study in combination with bevacizumab (Avastin®) in patients with Grade IV malignant glioma (glioblastoma), and has received Orphan Drug designation for marizomib in glioblastoma in the United States from the FDA. In addition, Triphase Accelerator is currently developing marizomib in combination with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma, and has received Orphan Drug designation for marizomib in multiple myeloma in the United States and the European Union. Triphase Accelerator is also evaluating an oral formulation in preclinical studies. Marizomib has not been approved for any use in any country. About Triphase Accelerator Triphase Accelerator is a private drug development company with a primary focus on oncology and with operations in Toronto and San Diego. Triphase Accelerator is dedicated to advancing novel compounds through Phase 2 proof-of-concept clinical studies using a unique, science-based, high-quality model that is faster and more cost-effective than traditional pharmaceutical and biotech industry drug development approaches. Triphase Accelerator was spun out of the Ontario Institute for Cancer Research (OICR), with support from the Fight Against Cancer Innovation Trust (FACIT), MaRS Innovation and MaRS. It has a strategic relationship with Celgene for marizomib. For more information, visit www.triphaseco.com or LinkedIn.


Zhou Y.-H.,University of California at Irvine | Hess K.R.,University of Texas M. D. Anderson Cancer Center | Raj V.R.,University of Arkansas for Medical Sciences | Yu L.,Ziren research LLC | And 3 more authors.
Biomarker Insights | Year: 2010

Background: Prognosis models established using multiple molecular markers in cancer along with clinical variables should enable prediction of natural disease progression and residual risk faced by patients. In this study, multivariate Cox proportional hazards analyses were done based on overall survival (OS) of 100 glioblastoma multiformes (GBMs, 92 events), 49 anaplastic astrocytomas (AAs, 33 events), 45 gliomas with oligodendroglial features, including anaplastic oligodendroglioma (AO, 13 events) and oligodendraglioma (O, 9 events). The modeling included two clinical variables (patient age and recurrence at the time of sample collection) and the expression variables of 13 genes selected based on their proven biological and/or prognosis functions in gliomas (ABCG2, BMI1, MELK, MSI1, PROM1, CDK4, EGFR, MMP2, VEGFA, PAX6, PTEN, RPS9, and IGFBP2). Gene expression data was a log-transformed ratio of marker and reference (ACTB) mRNA levels quantified using absolute real-time qRT-PCR. Results: Age is positively associated with overall grade (4 for GBM, 3 for AA, 2_1 for AO_O), but lacks significant prognostic value in each grade. Recurrence is an unfavorable prognostic factor for AA, but lacks significant prognostic values for GBM and AO_O. Uni-variate models revealed opposing prognostic effects of ABCG2, MELK, BMI1, PROM1, IGFBP2, PAX6, RPS9, and MSI1 expressions for astrocytic (GBM and AA) and oligodendroglial tumors (AO_O). Multivariate models revealed independent prognostic values for the expressions of MSI1 (unfavorable) in GBM, CDK4 (unfavorable) and MMP2 (favorable) in AA, while IGFBP2 and MELK (unfavorable) in AO_O. With all 13 genes and 2 clinical variables, the model R2 was 14.2% (P = 0.358) for GBM, 45.2% (P = 0.029) for AA, and 62.2% (P = 0.008) for AO_O. Conclusion: The study signifies the challenge in establishing a significant prognosis model for GBM. Our success in establishing prognosis models for AA and AO_O was largely based on identification of a set of genes with independent prognostic values and application of standardized gene expression quantification to allow formation of a large cohort in analysis. © the author(s), publisher and licensee Libertas Academica Ltd.


Gilbert M.,Neuro Oncology | Vogelbaum M.A.,Cleveland Clinic
Journal of Neuro-Oncology | Year: 2010

Atypical (WHO grade II) meningiomas occupy an intermediate risk group between benign (WHO grade I) and anaplastic (WHO grade III) meningiomas. Although grade II meningiomas have traditionally been recognized in only about 5% of cases, after changes in diagnostic criteria with the current 2007 WHO standards, they now comprise approximately 20-35% of all meningiomas. Given the magnitude of this change, much work is now needed to solidify the adoption of these standards, to render inter-observer and inter-institutional comparisons more uniform, and to more carefully define the incidence of grade II histology. However, it is clear that they carry a several-fold increased risk of recurrence, as well as an increased rate of mortality. We will discuss the definition, diagnosis, and treatment of patients with atypical meningioma; review the current phase II cooperative trials; and draw attention to some questions timely for pre-clinical and clinical research. © 2010 Springer Science+Business Media, LLC.

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