A 4-Gene Signature Associated with Clinical Outcome in High-Grade Gliomas

Tayrac, Marie de; Aubry, Marc; Saïkali, Stéphan; Etcheverry, Amandine; Surbled, Cyrille; Guénot, Frédérique; Galibert, Marie‐Dominique; Hamlat, Abderrahmane; Lesimple, Thierry; Quillien, Véronique; Menei, Philippe; Mosser, Jean

doi:10.1158/1078-0432.ccr-10-1126

Cited by 67 publications

(65 citation statements)

References 35 publications

(48 reference statements)

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“…Global gene expression of gliomas has been extensively studied over the past decade [31,40,105,108,146]. The best known expression-based molecular classification subdivides glioblastoma and anaplastic astrocytoma into 3 classes (Proneural, Mesenchymal or Proliferative) or glioblastomas into 4 subtypes (Proneural, Neural, Classical and Mesenchymal), which are largely comparable [40,108,146].…”

Section: Comprehensive Genome Analysismentioning

confidence: 99%

Diffusely infiltrating astrocytomas: pathology, molecular mechanisms and markers

Ichimura¹,

Narita²,

Hawkins

2015

Acta Neuropathol

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Diffusely infiltrating astrocytomas include diffuse astrocytomas WHO grade II and anaplastic astrocytomas WHO grade III and are classified under astrocytic tumours according to the current WHO Classification. Although the patients generally have longer survival as compared to those with glioblastoma, the timing of inevitable malignant progression ultimately determines the prognosis. Recent advances in molecular genetics have uncovered that histopathologically diagnosed astrocytomas may consist of two genetically different groups of tumours. The majority of diffusely infiltrating astrocytomas regardless of WHO grade have concurrent mutations of IDH1 or IDH2, TP53 and ATRX. Among these astrocytomas, no other genetic markers that may distinguish grade II and grade III tumours have been identified. Those astrocytomas without IDH mutation tend to have a distinct genotype and a poor prognosis comparable to that of glioblastomas. On the other hand, diffuse astrocytomas that arise in children do not harbour IDH/TP53 mutations, but instead display mutations of BRAF or structural alterations involving MYB/MYBL1 or FGFR1. A molecular classification may thus help delineate diffusely infiltrating astrocytomas into distinct pathogenic and prognostic groups, which could aid in determining individualised therapeutic strategies.

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Section: Comprehensive Genome Analysismentioning

confidence: 99%

Diffusely infiltrating astrocytomas: pathology, molecular mechanisms and markers

Ichimura¹,

Narita²,

Hawkins

2015

Acta Neuropathol

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“…As part of the ''Grand Ouest Glioma Project'', funded by the French National Institute of Cancer, whose objective was to study tumor heterogeneity in GB [15][16][17][18][19][20][21][22], we performed a multidisciplinary analysis of the PBZ with a variety of techniques including radiology, histopathology, flow cytometry, omic analyses and primary cell cultures. The resulting PBZ profiles were compared with those of GB tumor zone (TZ) and normal brain samples to identify characteristics specific to the PBZ.…”

Section: Introductionmentioning

confidence: 99%

Characterizing the peritumoral brain zone in glioblastoma: a multidisciplinary analysis

et al. 2015

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Glioblastoma (GB) is the most frequent and aggressive type of primary brain tumor. Recurrences are mostly located at the margin of the resection cavity in the peritumoral brain zone (PBZ). Although it is widely believed that infiltrative tumor cells in this zone are responsible for GB recurrence, few studies have examined this zone. In this study, we analyzed PBZ left after surgery with a variety of techniques including radiology, histopathology, flow cytometry, genomic, transcriptomic, proteomic, and primary cell cultures. The resulting PBZ profiles were compared with those of the GB tumor zone and normal brain samples to identify characteristics specific to the PBZ. We found that tumor cell infiltration detected by standard histological analysis was present in almost one third of PBZ taken from an area that was considered normal both on standard MRI and by the neurosurgeon under an operating microscope. The panel of techniques used in this study show that the PBZ, similar to the tumor zone itself, is characterized by substantial inter-patient heterogeneity, which makes it difficult to identify representative markers. Nevertheless, we identified specific alterations in the PBZ such as the presence of selected tumor clones and stromal cells with tumorigenic and angiogenic properties. The study of GB-PBZ is a growing field of interest and this region needs to be characterized further. This will facilitate the development of new, targeted therapies for patients with GB and the development of approaches to refine the per-operative evaluation of the PBZ to optimize the surgical resection of the tumor.

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“…Although molecular genetic abnormalities of glioblastoma (1-3) have been described and their associations with phenotypic features and prognosis have been reported (4)(5)(6)(7), translation to improve therapeutic response has lagged, and outcomes remain poor. Specifically, median progression-free survival (PFS) and overall survival (OS) for patients with newly diagnosed glioblastoma are only 6.9 and 14.6 months, respectively, despite maximum safe resection and temozolomide chemoradiation (8).…”

Section: Introductionmentioning

confidence: 99%

A Phase I/II Trial of Pazopanib in Combination with Lapatinib in Adult Patients with Relapsed Malignant Glioma

Reardon

Groves

Wen

et al. 2013

Clinical Cancer Research

108

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Purpose: Increased mitogenic signaling and angiogenesis, frequently facilitated by somatic activation of EGF receptor (EGFR; ErbB1) and/or loss of PTEN, and VEGF overexpression, respectively, drive malignant glioma growth. We hypothesized that patients with recurrent glioblastoma would exhibit differential antitumor benefit based on tumor PTEN/EGFRvIII status when treated with the antiangiogenic agent pazopanib and the ErbB inhibitor lapatinib.Experimental Design: A phase II study evaluated the antitumor activity of pazopanib 400 mg/d plus lapatinib 1,000 mg/d in patients with grade 4 malignant glioma and known PTEN/EGFRvIII status not receiving enzyme-inducing anticonvulsants (EIAC). The phase II study used a two-stage Green-Dahlberg design for futility. An independent, parallel phase I component determined the maximum-tolerated regimen (MTR) of pazopanib and lapatinib in patients with grade 3/4 glioma receiving EIACs.Results: The six-month progression-free survival (PFS) rates in phase II (n ¼ 41) were 0% and 15% in the PTEN/EGFRvIII-positive and PTEN/EGFRvIII-negative cohorts, respectively, leading to early termination. Two patients (5%) had a partial response and 14 patients (34%) had stable disease lasting 8 or more weeks. In phase I (n ¼ 34), the MTR was not reached. On the basis of pharmacokinetic and safety review, a regimen of pazopanib 600 mg plus lapatinib 1,000 mg, each twice daily, was considered safe. Concomitant EIACs reduced exposure to pazopanib and lapatinib.Conclusions: The antitumor activity of this combination at the phase II dose tested was limited. Pharmacokinetic data indicated that exposure to lapatinib was subtherapeutic in the phase II evaluation. Evaluation of intratumoral drug delivery and activity may be essential for hypothesis-testing trials with targeted agents in malignant glioma.

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A 4-Gene Signature Associated with Clinical Outcome in High-Grade Gliomas

Cited by 67 publications

References 35 publications

Diffusely infiltrating astrocytomas: pathology, molecular mechanisms and markers

Diffusely infiltrating astrocytomas: pathology, molecular mechanisms and markers

Characterizing the peritumoral brain zone in glioblastoma: a multidisciplinary analysis

A Phase I/II Trial of Pazopanib in Combination with Lapatinib in Adult Patients with Relapsed Malignant Glioma

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