Glioblastoma Stem Cells: A Neuropathologist's View

McLendon, Roger E.; Rich, Jeremy

doi:10.1155/2011/397195

Cited by 23 publications

(26 citation statements)

References 63 publications

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“…These tumors are histologically and molecularly diverse, exhibiting heterogeneity both between patients and within individual tumors [1,2]. This heterogeneity has confounded development of effective therapies.…”

Section: Introductionmentioning

confidence: 99%

Glioma IL13Rα2 Is Associated with Mesenchymal Signature Gene Expression and Poor Patient Prognosis

et al. 2013

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A major challenge for successful immunotherapy against glioma is the identification and characterization of validated targets. We have taken a bioinformatics approach towards understanding the biological context of IL-13 receptor α2 (IL13Rα2) expression in brain tumors, and its functional significance for patient survival. Querying multiple gene expression databases, we show that IL13Rα2 expression increases with glioma malignancy grade, and expression for high-grade tumors is bimodal, with approximately 58% of WHO grade IV gliomas over-expressing this receptor. By several measures, IL13Rα2 expression in patient samples and low-passage primary glioma lines most consistently correlates with the expression of signature genes defining mesenchymal subclass tumors and negatively correlates with proneural signature genes as defined by two studies. Positive associations were also noted with proliferative signature genes, whereas no consistent associations were found with either classical or neural signature genes. Probing the potential functional consequences of this mesenchymal association through IPA analysis suggests that IL13Rα2 expression is associated with activation of proinflammatory and immune pathways characteristic of mesenchymal subclass tumors. In addition, survival analyses indicate that IL13Rα2 over-expression is associated with poor patient prognosis, a single gene correlation ranking IL13Rα2 in the top ~1% of total gene expression probes with regard to survival association with WHO IV gliomas. This study better defines the functional consequences of IL13Rα2 expression by demonstrating association with mesenchymal signature gene expression and poor patient prognosis. It thus highlights the utility of IL13Rα2 as a therapeutic target, and helps define patient populations most likely to respond to immunotherapy in present and future clinical trials.

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Section: Introductionmentioning

confidence: 99%

Glioma IL13Rα2 Is Associated with Mesenchymal Signature Gene Expression and Poor Patient Prognosis

et al. 2013

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“…Finally, the EphA3 receptor can be readily detected in GBM-infiltrating cells of monocytic origin, tumor-associated macrophages (TAM) (Figure 3). Thus, collectively, IL-13RA2, EphA2, and EphA3 are expressed in several GBM compartments documented to be involved in tumor progression and/or resistance to therapies (18,19). Of importance, ephrin-A5 (eA5) binds EphA2 and EpA3 receptors and also the EphB2 (17,65,66) receptor, all present in abundance in GBM tumors, but not in normal brain.…”

Section: Targeted Cytotoxic Therapy Of Gbmmentioning

confidence: 99%

“…Moreover, GSCs may play an important role in GBM progression/recurrence and resistance to therapies like chemotherapy or radiation (18,19). Recently, four genomic subtypes of GBM were delineated: proneural, neural, mesenchymal, and classical (20,21), supportive of the complex pathobiological nature of GBM.…”

Section: Introductionmentioning

confidence: 99%

Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part I: Targeted Cytotoxic Therapy

2017

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Glioblastoma (GBM), a primary brain tumor, remains an unmet medical need. One of the major obstacles to GBM treatment is the adequate properties of drugs. Complex pathobiology of GBM, including local invasion and intratumoral heterogeneity, represent major challenges to generating effective therapies. We discuss here the design of targeted cytotoxic drugs with an increased access to tumors and pathophysiologically important tumor compartments. Our research and others' have shown that interleukin 13 receptor alpha 2 (IL-13RA2), EphA2, and EphA3 receptors are overexpressed in most patients with GBM, but not in normal brain, and also in spontaneous canine high-grade gliomas like GBM, an excellent translational model of GBM. These receptors and also the EphB2 receptor are overexpressed and are functional in several GBM compartments involved Delivering Cytotoxic Therapies to Glioblastoma 342 in tumor progression and/or resistance to therapies. We pursue the novel idea of targeting all four receptors with one targeted cytotoxic compound (QUAD-CTX). We are constructing a molecularly targeted anti-GBM drug that (i) may not require patient prescreening, (ii) will attack most tumor compartments known to be pathobiologically important, and (iii) performs these functions in one pharmaceutical entity, so it will be suitable for monotherapy. We thus wish to take advantage of a unique opportunity to produce an off-the-shelf, highly specific, molecularly targeted drug candidate suitable to treat perhaps even all patients with GBM. We envision that this "molecular resection" will translate into clear-cut durable responses in patients suffering from this dreadful disease.

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“…Because these stem cells appear to have a low mitotic activity, they are difficult to target by radiotherapy and conventional chemotherapy. For recent reviews on glioblastoma stem cells the reader is referred to Huang et al (2010) and McLendon and Rich (2010). Ignatova et al (2002) firstly described cells with stem-like properties in human cortical glial tumors.…”

Section: Stem Cells In Glioblastoma Multiformementioning

confidence: 99%