Successful Examples Include The Selective Targeting Of C-kit By Imatinib In Gastrointestinal Stromal

The importance of some tyrosine kinases

Protein tyrosine kinases, such as EGFR, PDGFR, C-Kit and C-Abl regulate a large range of proteins implicated in processes including growth, metabolism and differentiation. They are divided into receptor and non-receptor tyrosine kinases, which initiate signaling processes by phosphorylation and dephosphorylation of a variety of downstream proteins including PI3K/Akt and members of the RAS/RAF/-mitogen-activated protein kinase (MAPK) signaling pathway. Progression to a higher grade glioma is related with an increase in multiple genetic alterations. The identification of genetic mutations in HGG tumours opened a whole field for possible new therapies, shifting away from the deregulated cell cycle control as the only target. Overexpression of these tyrosine kinases leads to elevated downstream neoplastic signalling, and may promote cancerous behaviour. Recent advances in our understanding of the signalling pathways of these growth factor receptors involving their downstream effectors, made these available as targets, and novel treatments have been developed, which led to some improvements, particularly in quality of life. Successful examples include the selective targeting of C-Kit by imatinib in gastrointestinal stromal tumours and C-Abl by imatinib in chronic myeloid leukaemia.Initial clinical trials of tyrosine kinase inhibitors (TKIs) in HGG have been disappointing and suggested TKIs show little correlation with the expression status of the individual components of the growth factor signal transduction pathways. However, therapeutic response can be affected by a number of factors, for example, the inability of the drug to reach its intended target at sufficient concentrations. Moreover, alternative or parallel signalling pathways may be active resulting in ineffectual pathway blockade with single agent therapy. In addition, classical end point determinants (e.g. overall survival), may not directly quantify the effect of TKIs on pathway inactivation.

Genetic heterogeneity and related inhibitors

HGG exhibit considerable genetic heterogeneity. Several studies have shown that de novo primary glioblastomas (1GBM) (WHO Grade IV) are genetically different from those which develop from a lower grade anaplastic astrocytomas (AAIII) (WHO Grade III) or secondary glioblastomas (2GBM) (WHO Grade IV). 1GBM often show amplification of EGFR as well as loss of CDKN2A and PTEN, while AAIII / 2GBM frequently have mutations in p53, lose functional Rb1 and display genetic alterations in PDGFR and IDH1. Considering the heterogeneity of these tumours, it is likely the intended molecular target may only be active in a subpopulation of patients. Therefore, selection of patients based on an expression profile of their individual signalling pathways might more accurately determine the efficacy of the TKI therapy being evaluated. Mellinghoff et al. have revealed in a clinical trial of recurrent HGG patients, significant correlation between erlotinib or gefitinib response and the co-expression of PTEN, EGFRvIII and over-expressed wild type EGFR. They found a subpopulation of patients co-expressing all three proteins responded to TKI therapy, quantified by reduced tumor volume on serial MRI. Conflicting results derived from subsequent studies emulating this clinical trial and highlight the need for further direct in vitro characterisation of TKI efficacy.