Glioblastoma multiforme (GBM) is the most common primary brain tumour and one of the most deadly forms of cancer. GBM can arise in previously healthy individuals (primary GBM) or result from the malignant transformation of lower-grade gliomas (secondary GBM). Primary and secondary GBMs display different molecular alterations, suggesting different signalling pathways in their development. The current knowledge in terms of signalling and molecular alterations typical of GBM is presented and discussed in this chapter. Briefly, the aberrant signalling pathways can be divided into those that affect growth factor signalling and those that deregulate the cell cycle pathways. The main growth factor alterations are those affecting PDGF, EGFR, VEGF, HGF/SF, integrins, MMPs/TIMPs, p21-RAS, PI3K-PTEN-AKT, JAK-STAT, and PKC. As for the cell cycle pathway alterations, some of the principal ones are those involving p53, Rb, and p16/cdk4/cyclinD/pRb. In addition, the mechanisms underlying some key GBM features such as angiogenesis and invasion deserve special attention considering the most recent therapeutic implications. A thorough presentation of the main undergoing and completed clinical trial with inhibitors of growth factors or aberrant pathways is provided in this chapter. Novel therapeutic agents include anti-PDGFR, anti-EGFR, anti-VEGF, anti-VEGFR, anti-SF/HGF molecules, inhibitors of integrins and metalloproteinases, and blocking agents of Ras, MTOR/PI3K, and PKC pathways. In the foreseeable future, patients with GBM will have a molecular characterization of their tumour and therapies might be tailored for each case.
Carrabba, G., Mukhopadhyay, D., Guha, A. (2010). Aberrant signalling complexes in GBMs: Prognostic and therapeutic implications. In K.R. Swapan (a cura di), Glioblastoma: Molecular Mechanisms of Pathogenesis and Current Therapeutic Strategies (pp. 95-129). Springer [10.1007/978-1-4419-0410-2_5].
Aberrant signalling complexes in GBMs: Prognostic and therapeutic implications
Carrabba, G;
2010
Abstract
Glioblastoma multiforme (GBM) is the most common primary brain tumour and one of the most deadly forms of cancer. GBM can arise in previously healthy individuals (primary GBM) or result from the malignant transformation of lower-grade gliomas (secondary GBM). Primary and secondary GBMs display different molecular alterations, suggesting different signalling pathways in their development. The current knowledge in terms of signalling and molecular alterations typical of GBM is presented and discussed in this chapter. Briefly, the aberrant signalling pathways can be divided into those that affect growth factor signalling and those that deregulate the cell cycle pathways. The main growth factor alterations are those affecting PDGF, EGFR, VEGF, HGF/SF, integrins, MMPs/TIMPs, p21-RAS, PI3K-PTEN-AKT, JAK-STAT, and PKC. As for the cell cycle pathway alterations, some of the principal ones are those involving p53, Rb, and p16/cdk4/cyclinD/pRb. In addition, the mechanisms underlying some key GBM features such as angiogenesis and invasion deserve special attention considering the most recent therapeutic implications. A thorough presentation of the main undergoing and completed clinical trial with inhibitors of growth factors or aberrant pathways is provided in this chapter. Novel therapeutic agents include anti-PDGFR, anti-EGFR, anti-VEGF, anti-VEGFR, anti-SF/HGF molecules, inhibitors of integrins and metalloproteinases, and blocking agents of Ras, MTOR/PI3K, and PKC pathways. In the foreseeable future, patients with GBM will have a molecular characterization of their tumour and therapies might be tailored for each case.
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