Advances in Treatment Options for High-grade Glioma
disappointing. Studies of erlotinib (EGFR), gefitinib (EGFR) and lapatinib (ErbB2/HER2, EGFR) have failed to demonstrate any significant survival benefit compared with historical controls.78–86
The combination of EGFR inhibitors with other therapies is discussed later in this article.
Potential reasons for lack of response include poor blood–brain barrier penetration, insufficient local tumour concentrations, coactivation of multiple TKIs,87
redundant signalling pathways and resistance. Irreversible EGFR inhibitors, such as BIBW 2992 and PF-00299804, could have better efficacy in GBM than gefitinib or erlotinib due to increased potency and better brain concentration. This newer class of EGFR inhibitors has been shown to circumvent mechanisms of response to gefitinib or erlotinib in non-small-cell lung cancer cells.88–93
mAb and vaccines that target EGFR are currently under investigation in GBM. Both nimotuzumab and cetuximab, a chimeric anti-EGFR human–mouse mAb, are now being studied in combination with RT and temozolomide as upfront GBM therapies. Preliminary results from a phase II clinical trial suggest that the addition of CDX-110, a peptide-based EGFRvIII vaccine, to standard therapy prolongs survival in patients with newly diagnosed GBM.94
However, since patients
were required to have gross total resections and EGFRvIII mutation in order to be eligible for the trial, they represent a highly selected group with good prognosis.
Platelet-derived Growth Factor
Platelet-derived growth factors (PDGF) are a pleiotropic family of peptides that signal through PDGFR to stimulate cellular functions including growth, proliferation and differentiation.95
Imatinib mesylate
(Gleevec), an inhibitor of PDGFR-α and β, Bcr-Abl, c-Fms and c-Kit tyrosine kinases, demonstrated activity in pre-clinical models of glioma.96
However, in clinical trials neither imatinib monotherapy97,98 nor imatinib in combination with hydroxyurea (a ribonucleoside diphosphate reductase inhibitor)99
has demonstrated clinically useful
activity in GBM. One explanation for the lack of efficacy is that imatinib is a substrate for the P-glycoprotein efflux pump that limits its intracranial distribution.100
Tandutinib and dasatinib, second-
generation PDGFR inhibitors with improved CNS penetration, are in clinical trials for recurrent HGG.
c-Met
AMG 102 is a fully human monoclonal antibody that selectively targets SF/HGF. A phase II study of AMG 102 in recurrent GBM was recently completed but failed to produce any benefit.102
A
recent study suggests that the combination of EGFR inhibitors and c-Met inhibitors may be more effective than either agent alone in phosphatase and tensin homologue (PTEN) null GBM.103
Trials of c-Met
TKIs such as XL184 are under way in GBM. Intracellular Signalling Kinases
As activation of several RTKs, including EGFR and PDGFR, converges at the Ras/MAPK and PI3K/Akt pathways, inhibiting these downstream molecules may be more efficacious than targeting individual RTKs.
In the Ras/MAPK pathway, potential targets include Raf, MEK and farnesyltransferase. An early step in activation of the Ras/MAPK pathway is localisation of Ras to the cell membrane, which depends
EUROPEAN NEUROLOGICAL REVIEW DNA Repair
Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that signals the presence of DNA breaks and facilitates DNA repair by engaging mechanisms such as base excision repair (BER).110
As PARP inhibitors
disrupt BER, an important mediator of TMZ resistance, these agents may enhance the antitumour effects of temozolomide against HGG. Two PARP inhibitors, BSI-201 and ABT-888, are being tested in combination with radiation and temozolomide for newly diagnosed GBM.
Glioma Stem Cells
Glioma stem cells (GSCs) are believed to represent a subpopulation of cells in the tumour with the ability to self-renew, proliferate and give rise to progeny of multiple neuroepithelial lineages.111 to treatment resistance in HGG.112,113
They may contribute Stem cells are predicted to be 53
Scatter factor/hepatocyte growth factor (SF/HGF) and its TKR c-Met play a role in cell growth, cell motility, morphogenesis and angiogenesis.101
on Ras farnesylation by the enzyme farnesyltransferase. Farnesyltransferase inhibitors (FTI) such as tipifarnib104
showed
modest activity as monotherapy in recurrent HGG and are now being studied in combination with temozolomide for HGG.
The Raf serine/threonine kinases are the main downstream effectors of Ras in the MAPK pathway. Sorafenib is an inhibitor of c-Raf kinase, but also inhibits pro-angiogenic RTKs including VEGFR-2, VGFRR-3, PDGFR-β, Flt-3, c-Kit and FGFR-1. Several trials of sorafenib in high- grade glioma are under way, although the preliminary results have been disappointing.
Several PI3K and Akt inhibitors are in development or early clinical trials. XL765, an inhibitor of PI3K and mTOR, is currently in a phase I clinical trial in combination with temozolomide for HGG. Studies of XL147 and BKM120 are planned. Akt inhibitors undergoing evaluation in HGG include perifosine and MK2206.
mTOR, a downstream molecule in the PI3K/Akt pathway, is also an attractive target for therapy.105
The mTOR inhibitor sirolimus
(rapamycin) and its analogues temsirolimus, everolimus and ridaforolimus are the most clinically advanced PI3K/Akt pathway inhibitors. Despite promising results from pre-clinical studies, temsirolimus monotherapy was not clinically active in recurrent GBM in two multicentre phase II clinical trials,106,107
inhibition of only the TORC1 component may result in the activation of Akt. An Akt inhibitor, such as perifosine or MK2206, or a combined PI3K/mTOR inhibitor, such as XL765, may ultimately prove more effective. Studies combining mTOR inhibitors with other targeted agents are discussed below.
New Molecular Targets Histone Deacetylases
Histone deacetylase (HDAC) inhibitors cause the growth arrest, differentiation or apoptosis of many transformed cells by altering transcription of various genes.108
Vorinostat is a small-molecule inhibitor
of most human class I and class II HDACs. Vorinostat demonstrated moderate clinical activity in a phase II study of patients with recurrent GBM with a PFS6 of 15.2%.109
The Adult Brain Tumour Consortium and
the North Central Cancer Treatment Group are now jointly conducting a trial of vorinostat with RT and temozolomide in patients with newly diagnosed HGG. Clinical trials combining HDAC inhibitors with other agents such as bortezomib, a proteosome inhibitor, or bevacizumab are currently under way in recurrent GBM. A more potent HDAC inhibitor, LBH589, is entering phase II studies in recurrent GBM.
possibly because
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