Brain Trauma Oncology
Figure 2: 56-year-old Woman with Left Parietal Glioblastoma Showing Response to Therapy with XL184
A B
(PDGFR) and c-Kit. In a phase II clinical trial for recurrent GBM, cediranib achieved a promising RR of 27% and PFS6 of 26%.58
As had been noted
in the bevacizumab studies, there was a striking steroid-sparing effect, and the drug was well-tolerated. Other multitargeted VEGFR agents include vandetanib (VEGFR and EGFR), sorafenib (VEGFR, Raf, c-Kit), sunitinib (VEGFR-2, PDFR, c-kit and Flt-3), pazopanib (VEGFR, PDGFR, c-Kit), XL184 (VEGFR and c-Met) and CT322.59
Unfortunately, the benefits of anti-angiogenesis therapy are transitory, and it has been suggested that the impressive radiographic responses observed in patients treated with bevacizumab may be the result of decreased permeability of the vasculature rather than a true antitumour effect (see Figure 2). Mechanisms of resistance to anti-angiogenic therapy are beginning to be elucidated.60,61
Some C D
In recurrent HGG patients who are treated with anti-angiogenesis agents, tumour progression is occasionally radiographically observed as an increase in non-enhancing hyper-
pre-clinical data suggest that blockade of VEGF-mediated angiogenesis may promote tumour infiltration by co-option of native vessels.62–65
intensity on T2-weighted or fluid-attenuated inverse recovery (FLAIR) magnetic resonance imaging (MRI). Some hypothesise that this may represent infiltrative tumour growth.66–70
XL184 is a vascular endothelial growth factor receptor and Met inhibitor. A: Axial T1 with contrast before therapy; B: Axial fluid-attenuated inverse recovery (FLAIR) before therapy; C: Axial T1 with contrast four weeks after therapy showing partial response; D: Axial FLAIR four weeks after therapy showing significant reduction in peritumoral oedema.
Anti-angiogenic Therapies
Vascular Endothelial Growth Factor Pathway Inhibitors Angiogenesis is important to the growth and proliferation of HGG and is mediated through several pathways, most notably VEGF.49–51 levels of VEGF expression are observed in more malignant tumours.
Higher
Targeting VEGF and VEGFR has been the focus of many recent clinical trials. As noted above, bevacizumab has shown promising activity in recurrent GBM and is now FDA-approved for this indication.40,52,53 Phase II studies of bevacizumab plus irinotecan have also demonstrated efficacy in AG with an RR of 55–66% and PFS6 of 56–61%.54,55
Bevacizumab is generally well-tolerated, with the most common side effects being fatigue, hypertension and proteinuria. Less common serious side effects include thromboembolism, haemorrhage and bowel perforation.
There is emerging evidence that inhibitors of angiogenesis may work synergistically with RT.21
Two large multicentre trials evaluating the
efficacy of adding bevacizumab to RT and temozolomide in newly diagnosed GBM patients are under way. Phase II studies of the regimen appear to be safe despite a possible increase in wound- healing complications.56
Treatment of HGG with bevacizumab
combined with a variety of targeted molecular agents is being studied as well.52
Another VEGF-pathway inhibitor currently in clinical trials for HGG is aflibercept (a VEGF decoy receptor that consists of a VEGF receptor fused to an immunoglobulin constant region).57
In addition to inhibitors
of VEGF such as bevacizumab and aflibercept, there are many small- molecule TKIs directed against VEGFR. Cediranib is an oral pan-VEGFR inhibitor that also has activity against platelet-derived growth factor
52
Due to the lack of assessment of non-enhancing tumour and other limitations with the standard Macdonald et al. criteria, the multidisciplinary Response Assessment in Neuro-Oncology (RANO) Working Group recently proposed updated response criteria for HGG.71 In addition, levels of basic fibroblast growth factor (bFGF) and stromal- derived growth factor 1 alpha (SDF-1α) increase in GBM patients when tumours escaped treatment with cediranib.72
These findings imply that
one may overcome resistance to anti-angiogenic agents by combining anti-VEGF/VEGFR therapy with agents that target tumour invasion, non-VEGF-pro-angiogenic signalling pathways such as the FGF pathway or vasculogenic pathways such as the SDF-1α pathway.
Integrins The αvβ3 and αvβ5 integrins are cell-surface receptors that promote endothelial cell migration and survival during angiogenesis.73 Cilengitide (EMD121974) competitively inhibits αvβ3 and αvβ5. Phase II trials showed a PFS6 of 15% and a median OS of 9.9 months when cilengitide was added to RT and temozolomide. Patients with methylated MGMT promoter had better responses.74
Based on the
favourable results of this trial, a multicentre phase III trial is under way using cilengitide in patients with newly diagnosed GBM with methylated MGMT promoter.
Receptor Tyrosine Kinases
Epidermal Growth Factor Receptor Inhibitors EGFR is the most commonly altered RTK in HGG.75
Approximately
20–30% of GBM have a constitutively active EGFR mutant known as EGFRvIII, and all of these EGFRvIII-expressing tumours also exhibit EGFR amplification or overexpression.76
Signalling through these
and other growth factor receptors activates fundamental signal transduction pathways such as the Ras/mitogen-activated protein kinase (MAPK) pathway and the PI3K/Akt/mTOR pathway, both of which promote cell proliferation.10 pathways upregulate VEGF.49,77
Additionally, many of these
While subsets of GBM patients have sustained responses to reversible TKIs that target EGFR, to date the studies have been largely
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