2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

ESTABLISHING TREATMENTS FOR GLIOBLASTOMA
Table 1. Single-Agent Targeted Therapies for Recurrent Glioblastoma
Agent Study Year Target
kinase inhibitor p16 INK4A and amplification of CDK 4,
primary glioblastoma typically has higher incidence of epidermal
growth factor receptor (EGFR) amplification with
inactivation of PTEN and p16 tumor suppression genes. In
contrast, secondary glioblastoma multiforme is characterized
by mutation of TP53 gene and more recently, almost
exclusively demonstrate mutations in the isocitrate dehydrogenase
(IDH) 1 and 2 genes.
Epidermal growth factor (EGF) and its receptor EGFR,
platelet-derived growth factor (PDGF) A and B and their
receptors PDGFR � and �, VEGF and its receptor (VEGFR),
insulin-like growth factor (IGF)-1 and IGF receptor (IGFR),
transforming growth factor (TGF)-�, fibroblast growth factor
(FGF), and hepatocyte growth factor (HGF) are thought to
be critical to the pathogenesis and survival of glioblastoma.
Activation of these tyrosine kinase receptors triggers three
major downstream pathways: mitogen-activated protein
kinase (MAPK); phosphoinositide 3 kinase (PI3K)/Akt; and
phospholipase C� (PLC�) and protein kinase C (PKC). These
signaling pathways regulate cell proliferation and differentiation
and prevent apoptosis, and are therefore logical
targets of treatment for glioblastoma.
Unfortunately, despite these molecular findings in a high
percentage of glioblastoma, as indicated in Table 1, studies
with single-agent signal transduction modulators demonstrated
only modest results at best. In particular, even in the
presence of amplification or mutation of EGFR, treatment
with a potent EGFR inhibitor such as erlotinib did not result
in a high response rate. Subsequent analyses suggested that
response to erlotinib occurred only when the downstream
component of the pathway was not already constitutively
activated as indicated by the presence of a functional PTEN
gene regulating Akt. 28 These results underscore the complex
nature of signal transduction modulation strategies with
pathway overlap and downstream effectors. Attempts and
combination regimens of signal transduction modulators has
been complicated by overlapping toxicities.
Antiangiogenic agents. One of the hallmarks of glioblastoma
is prominent angiogenesis, making this component of
tumor biology a logical target. The newly formed blood
vessels are often poorly developed, with incomplete tight
junction between endothelial cells and tortuous paths with
blind loops. These features lead to peritumoral edema and
account for much of the imaging enhancement by leakage of
systemic administration of contrast material before either
computed tomography or magnetic resonance imaging. A
Trial
Phase
No. of
Patients
6-Month
Progression-Free
Survival (%)
Erlotinib van den Bent29 2009 EGFR II 110 11
Gefitinib Rich30 2004 EGFR II 53 13; 14
Imatinib Raymond31 2008 C-ABL, C-KIT, PDGFR II 51 16
Pazopanib Iwamoto32 2010 VEGFR, PDGFR II 35 3
Vorinostat Galanis33 2009 HDAC II 66 15
Tipifarnib Cloughesy34 2006 Farnesyltransferase II 67 12
Galanis
Temsirolimus
35 2005 II 65 8
Chang36 2005 mTOR 41 3
Wick
Enzastaurin
27 2010 III 174 11
Kreisl37 2010 PKC I/II 72 7
Abbreviations: EGFR, epidermal growth factor receptor; C-ABL, a non-receptor protein tyrosine kinase; C-KIT, a cell surface protein that binds stem cell factor;
C-MET, met proto-oncogene; PDGFR, platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor; HDAC, histone deacetylase; mTOR,
mammalian target of rapamycin; PKC, protein kinase C.
variety of antiangiogenic agents have been tested, as outlined
in Table 2.
Bevacizumab, a humanized monoclonal antibody, works
by sequestering the circulating ligand VEGF-A, resulting in
angiogenesis inhibition. Several phase II studies have been
performed in patients with recurrent glioblastoma. Most
studies demonstrate a response rate ranging from 25% to
40% and a 6-month progression-free survival in the same
range. Importantly, nearly all patients receiving bevacizumab
are able to either reduce or stop corticosteroid use.
These findings, most notably in a multicenter randomized
noncomparative phase II trial, led to the accelerated approval
of bevacizumab for patients with recurrent glioblastoma.
39
A variety of other antiangiogenic agents have been evaluated
including aflibercept (VEGF-Trap), a decoy VEGFR
fused to the Fc portion of an immunoglobulin molecule.
However, results of a phase II trial in recurrent glioblastoma
revealed only modest activity. Cediranib is a small-molecule
tyrosine kinase inhibitor of the spectrum of VEGFR that
showed early efficacy, but a subsequent phase III trial with
lomustine failed to demonstrate added benefit from the
cediranib. Carbozantinib (XL184), a small-molecule agent
that targets both VEGFR and c-Met also showed efficacy in
early studies, but systemic toxicities often precluded extended
use. Cilengitide is a novel antiangiogenic agent that
targets the � v� 3 integrin that is required for endothelial cell
migration for neovascularization. There may be additional
tumor signal pathway effects that further enhance efficacy.
Single-agent activity has been modest, but as described
herein, synergistic efficacy with chemoradiation is being
tested in newly diagnosed glioblastoma.
Table 2. Antiangiogenic Therapies Investigated for
Recurrent Glioblastoma
Agent Study Year Target
Trial
Phase
No. of
Patients
6-Month
Progression-Free
Survival (%)
Cediranib Batchelor 38 2010 pan-VEGFR II 31 26
Bevacizumab Friedman 39 2009 VEGF-A II 85 36
Cilengitide Reardon 40 2008 � v� 3 integrin 81 15
Gilbert 41 2011 � v� 5 integrin II 26 12
XL-184 Wen 42 2010 VEGFR, C-MET II 124 21
Abbreviations: VEGFR, vascular endothelial growth factor receptor; C-MET,
met proto-oncogene; EGFR, epidermal growth factor receptor; VEGF, vascular
endothelial growth factor.
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