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Glioblastoma

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults and one of the most lethal human cancers. GBMs are part of the spectrum of malignant gliomas, which are thought to arise from the intrinsic glial cells of the brain, although recent studies have questioned this assumption. GBM is not a surgically curable disease; tumor cells invade the surrounding brain, rendering complete surgical resection virtually impossible. In addition, GBM tumors are among the most resistant to radiation and cytotoxic chemotherapy. Therefore, GBM patients survive, on average, 12-15 months despite aggressive surgical resection and conventional therapy. New treatment approaches are desperately needed.

Over the past two decades, a number of recurring molecular alterations have been identified in gliomas and particularly in GBMs, which enable characterization of diffuse gliomas and a better understanding of glioma landscape and pathways that are disrupted in this malignancy. Results from Health’s Cancer Genome Atlas (TCGA) studies and contributions made by individual labs have revealed a number of genetic abnormalities and thus, specific patterns have emerged that indicate the involvement of specific molecular and signaling pathways in the development and progression of glial tumors. These include loss of CDKN2A, RB1, and TP53 tumor suppressor genes, in addition to alterations in genes involved in these pathways or regulated by these tumor suppressor proteins. Mutations in the ATRX, IDH1, and p53 genes are considered molecular hallmarks of diffuse and anaplastic astrocytomas as well as secondary GBMs, and interestingly, TP53 mutations also occur in nearly all instances of the rare giant cell GBM variant. Integrated genomic studies have revealed that in the majority of GBMs, the functions of p53 (87 % of GBM patients) and retinoblastoma (Rb) (78 % of GBM patients) pathways are disrupted either by mutations or gene copy number alterations. Moreover, mutations in genes encoding upstream regulators of Rb, but not necessarily the RB1 gene itself, have been known for some time to be characteristic of gliomas. For instance, in a fraction of anaplastic gliomas and particularly in GBMs, the CDKN2A gene is homozygously deleted; CDKN2A locus encodes both Arf and Ink4A proteins, which are crucial activators of Rb and p53, respectively. Furthermore, upstream repressors of p53 and Rb signaling pathways, such as Cdk4 (phosphorylates and inactivates Rb) and Mdm2 (p53 inhibitor), are often up-regulated by gene amplification, suggesting the involvement of alternative mechanisms for disruption of p53 and Rb signaling pathways, as observed in the majority of GBMs.

In addition, Brennan et al. performed unsupervised hierarchical clustering of targeted proteomic analysis of 57 signaling proteins, including posttranslationally modified proteins that cluster within these known signaling pathways, in a set of 20 clinical GBM samples. Their research revealed the presence of three signaling subclasses: (a) an EGFR subgroup characterized by EGFR activation and strong PI3K signaling, among other downstream effectors; (b) a PDGF subgroup characterized by PDGFR signaling; and (c) an NF1 group whose downstream signaling effectors were less well defined. An analysis of PDGFR, EGFR, and NF1 alterations with TCGA expression profile subclasses showed that PDGFRA, EGFR, and NF1 lesions are mutually exclusive. These observations build on the central finding of the TCGA, namely that genomic alterations in GBM cluster around potentially therapeutically targetable core pathways (RTK/RAS/PI3K, p53, and RB1) to define biologically meaningful and perhaps differentially targetable subclasses of GBMs.

As we learn more about the biology of GBM and its aberrant signaling pathways, the neuro-oncology community has begun to investigate the role of molecularly targeted agents inhibiting these pathways. Most of the targeted agents are small-molecule tyrosine kinase inhibitors or monoclonal antibodies. The signaling pathways targeted include tumor growth factor pathways, angiogenesis pathways, and the intracellular signaling pathways that lie downstream of both. A wide variety of targeted agents are being studied in the preclinical setting and in clinical trials.

Creative Biogene, as a leading biotechnology company, is able to offer various glioblastoma pathway related products including stable cell lines, viral particles and clones for your pathogenesis study and drug discovery projects.

References:

  1. Cloughesy T F, et al. Glioblastoma: from molecular pathology to targeted treatment. Annual Review of Pathology: Mechanisms of Disease, 2014, 9: 1-25.
  2. Aldape K, et al. Glioblastoma: pathology, molecular mechanisms and markers. Acta neuropathologica, 2015, 129(6): 829-848.
  3. Clarke J, et al. Recent advances in therapy for glioblastoma. Archives of neurology, 2010, 67(3): 279-283.

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