Neurosurg Focus 37 (6):E10, 2014
©AANS, 2014
Targeting MET for glioma therapy
Ahmed J. Awad, M.D.,1 Terry C. Burns, M.D., Ph.D., 2 Ying Zhang, Ph.D., 3
and Roger Abounader, M.D., Ph.D. 3
Departments of 1Neurosurgery and 3Microbiology, Immunology, and Cancer Biology, University of Virginia,
Charlottesville, Virginia; and 2Department of Neurosurgery, Stanford University School of Medicine,
Stanford, California
Glioblastoma multiforme is the most common and most lethal of all primary brain tumors. Even with the standard therapy, life expectancy is still poor, with an average survival of approximately 14 months following initial
diagnosis. Hence, there is an urgent need for novel treatment strategies that inhibit proliferation and angiogenesis
in high-grade gliomas. One such strategy consists of inhibiting receptor tyrosine kinases, including MET and/or its
ligand hepatocyte growth factor (HGF). Because of their widespread involvement in human cancer, HGF and MET
have emerged as promising therapeutic targets, and some inhibitory agents that target them have already entered
clinical trials. In this paper, the authors highlight recent evidence implicating HGF/MET pathway deregulation in
glioblastoma multiforme, discuss therapeutic approaches to inhibit HGF/MET signaling, and summarize ongoing
clinical trials targeting this pathway.
(http://thejns.org/doi/abs/10.3171/2014.9.FOCUS14520)
Key Words • MET • hepatocyte growth factor • glioblastoma multiforme
G
multiforme (GBM; WHO Grade IV)
is the most common and most lethal of all primary
brain tumors. The incidence rate of GBM in the
US is estimated to be 2.69 per 100,000 persons per year,
comprising 12%–20% of all brain tumors.21,54 Even with
the standard triad of surgery, chemotherapy, and radiation therapy, life expectancy is still poor, with an average
survival of approximately 14 months following initial diagnosis.28 Hence, there is an urgent need for novel treatment strategies that inhibit proliferation and angiogenesis
in high-grade gliomas. One such strategy consists of inhibiting receptor tyrosine kinases (RTKs).
Receptor tyrosine kinases are cell-surface receptors
that regulate normal cellular processes through regulation by growth factors, cytokines, and hormones. There
are 90 unique tyrosine kinase genes identified in the human genome, of which 58 are the transmembrane receptor type that can be classified into approximately 20 subfamilies.9 In addition to their physiological roles, RTKs
are key determinants of malignancy in many human solid
tumors, including non–small cell lung cancer, colorectal
adenocarcinoma, prostate adenocarcinoma, squamous
cell carcinoma of the head and neck, GBM, and gastric,
pancreatic, breast, ovarian, and cervical cancers.62 Aclioblastoma
Abbreviations used in this paper: GBM = glioblastoma multiforme; GSC = glioma stem cell; HGF = hepatocyte growth factor;
mAb = monoclonal antibody; RTK = receptor tyrosine kinase.
Neurosurg Focus / Volume 37 / December 2014
cording to The Cancer Genome Atlas genetic screening,
86% of human GBM samples harbor at least one genetic
aberration in RTK pathways.15 These include frequent
activating mutations in EGFR, ERBB2, PDGFRA, and
MET. Additionally, overexpression of ligand and/or receptor and coexpression of both (autocrine loop formation) are frequent events in cancers, including GBM, and
have been associated with increased malignancy and
worse patient survival.35,45,61 Because of their critical roles
in cancers, RTKs have become an attractive therapeutic
target in cancers in general and for gliomas in particular.
MET is an RTK protein encoded by the MET protooncogene, and functions as a membrane receptor that is
essential for embryonic development. MET and its ligand
hepatocyte growth factor (HGF), also known as scatter
factor (SF), are important mediators of malignancy in
human cancers, including brain tumors. Aberrant MET
activation in brain tumors enhances tumor growth by inducing cell proliferation, promoting tumor angiogenesis,
inhibiting cell death, inducing tumor invasion, and promoting cancer stem cells.3,29,37,38,43,56 Activation of MET is
associated with poor clinical outcomes.7,47 Inhibiting endogenous HGF and/or MET in experimental brain tumor
models inhibits glioma growth and angiogenesis and promotes apoptosis.2,13 The HGF/MET oncogenic effects are
mediated by a complex downstream signaling network:
most importantly, the Ras/MAPK and PI3K/Akt pathways.4,55 Because of their widespread involvement in hu1
A. J. Awad et al.
man cancer, HGF and MET have emerged as promising
therapeutic targets, and some inhibitory agents that target
them have already entered clinical trials. We highlight
recent evidence implicating HGF/MET pathway deregulation in GBM, discuss therapeutic approaches to inhibit
HGF/MET signaling, and discuss ongoing clinical trials
targeting this pathway.
Structure and Signal Transduction
of MET and HGF
Structure of HGF and MET
The human MET proto-oncogene is located in the
7q31 locus of chromosome 7.11 MET is initially synthesized as a 170-kD glycosylated single-chain precursor
that is cleaved into a 50-kD extracellular a chain and a
140-kD transmembranous b chain that are linked together by a disulfide bridge.23 The b chain contains the cytoplasmic kinase domain and a protein docking site that
contains 2 tyrosine residues essential for downstream signaling.8,22 The gene encoding the MET ligand HGF is located on chromosome 7q21.1.60 It produces a single-chain
inactive precursor that is cleaved by serine proteases into
a 69-kD a chain and a 34-kD b chain linked by a disulfide bond.48,53
MET-Dependent Signal Transduction
Binding of HGF to MET induces MET kinase catalytic activity, which triggers the phosphorylation of
mul­tiple residues in the receptor’s intracellular domain.
When tyrosines Y1349 and Y1356 are phosphorylated,
numerous substrates are recruited and bind to the MET
docking site, including Gab1, Grb2, PI3K, Shc, Src, and
others.44,55,64 This leads to the activation of downstream
signal transduction pathways including the Ras/MAPK,
PI3K/Akt, and STAT pathways. These interacting pathways mediate a diversity of cellular behaviors, including
(Fig. 1) the following.
1) Activation of Ras/MAPK induces cell migration and
proliferation.42,63 HGF triggers a cell survival signal through
PI3K, Akt, Pak1, and NFkB that mediates resistance to apoptosis.12,19,20,41,67
2) The complex morphogenic phenomenon of branched
tubules formation requires both Ras/MAPK and PI3K/Akt activation.8
3) The STAT pathway is necessary for endothelial tubule
morphogenesis and endothelial cell proliferation, and has been
implicated in MET-induced angiogenesis.10,52
4) HGF indirectly activates alternative RTKs such as EGFR
by upregulating expression of EGFR ligands TGF-a and
HB-EGFL.57
5) b-catenin translocates into the nucleus following MET
activation and participates in regulation of gene expression.49
6) Notch signaling is activated by the survival signal mediated through MET and Akt.24
7) MET enhances the so-called stemness of tumor-initiating
cancer stem cells that contribute to tumor propagation and treatment resistance.29,43
2
Fig. 1. Schematic showing the MET pathway and functions in gliomas. Reprinted in modified form by permission from Macmillan Publishers Ltd: Nature Reviews Molecular Cell Biology, Birchmeier C, et al.:
Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915–925,
copyright 2003.
HGF and MET Expression in Gliomas
MET is frequently overexpressed in GBM, and some
gliomas show HGF autocrine activation of the MET signaling pathway.32 Several studies have found that HGF
and MET are expressed at higher levels in human gliomas
than in control brain tissue, and that expression levels correlate with tumor grade.32,58 The HGF content was measured in 74 clinical samples obtained from human lowgrade and high-grade gliomas. The HGF expression in
high-grade (WHO Grade III–IV) tumors was significantly higher than in low-grade (WHO I–II) tumors.38 Similarly, coexpression of HGF and MET is observed more
frequently in Grade IV GBM than in low-grade glioma,
consistent with the contribution of an HGF/MET autocrine loop to malignant progression in these tumors.32,51
HGF and MET are also overexpressed in glioma endothelial cells, consistent with the well-described role of
HGF as a potent angiogenic factor. Several studies have
shown that MET and HGF are expressed and functional
Neurosurg Focus / Volume 37 / December 2014
Targeting MET for glioma therapy
in neuromicrovascular and brain tumor vascular cells.
Moderate to high levels of immunoreactive and biologically active HGF were found in cultured brain-derived
microvascular endothelial cells.58 Using double immunofluorescence staining and quantitative confocal laser
scanning microscopy, it was also shown that the intensity
of HGF and MET staining in human primary brain tumors is prevalent in both the infiltrating tumor cells and
hyperplastic endothelium. Additionally, prominent HGF
and MET immunostaining was observed in the vasculature of GBM, whereas less intense MET and HGF immunostaining was observed in areas of neovascularization
within low-grade astrocytoma (WHO Grade I and II) and
anaplastic astrocytoma (WHO Grade III).32 Using in situ
hybridization, strong HGF mRNA expression was also
detected in the majority of tumor cells and in vascular
endothelial cells in GBM specimens, but was less prevalent in anaplastic astrocytoma, diffuse astrocytoma, pilocytic astrocytoma, and normal brain. MET immunoreactivity was also observed in GFAP-expressing astrocytic
tumor cells and endothelial cells as well as in a subset
of microglia/macrophages. Other experimental evidence
points to autocrine and paracrine endothelium MET activation as a contributor to tumor angiogenesis.33
Oncogenic Effects of MET in Gliomas
Cell Proliferation
Activation of MET induces glioma tumor cell and
endothelial cell proliferation. Treatment of glioma cells
with exogenous recombinant HGF, or forced overexpression of HGF in glioma cells induce tumor cell and tumor
endothelial cell DNA synthesis and proliferation.37,39,58
Conversely, inhibiting endogenous HGF or MET expression in glioma cells with U1snRNA/ribozymes, the HGF
antagonist NK4, or an anti-HGF neutralizing monoclonal antibody (mAb) inhibits tumor cell proliferation.2,13,31
Moreover, inhibiting HGF and MET expression in human
glioma xenografts reduces tumor cell proliferation.2,5
HGF/MET has been found to act at least in part through
c-Myc activation of G1/S cell cycle progression.63
Cell Survival
HGF is a potent inhibitor of apoptosis and chemotherapy- and radiotherapy-induced cell death in glioma
tumor cells. Treating human glioblastoma cells with HGF
partially inhibits the cytotoxic effects of gamma irradiation, cisplatin, camptothecin, Adriamycin, and Taxol.12
Similarly, forced expression of HGF in rat intracranial
gliosarcomas reduces tumor cell sensitivity to in vivo
gamma irradiation.12 Conversely, inhibiting endogenous
HGF in either glioma cells or glioma xenografts leads
to induction of apoptosis and cell death, with increased
cleaved caspase-3 expression in cells and in xenografts.2,12
Inhibiting endogenous HGF and MET synergizes with radiation therapy in inhibiting the in vivo growth of GBM
xenografts.36 This provides a rationale for using antiHGF/MET therapies to sensitize brain tumors to radiation therapy.
Neurosurg Focus / Volume 37 / December 2014
Cell Migration and Invasion
Hepatocyte growth factor stimulates cerebral microvascular endothelial cell motility and induces chemotactic
migration of glioma cells.14,38 Conversely, MET inhibition
via anti-MET U1snRNA/ribozymes attenuated glioblastoma cell migration in a 2D scratch assay.2 Additionally,
treating glioma cells with HGF enhances invasiveness in
MET-positive malignant glioma tumor cells.65 Two studies have demonstrated that HGF increases invasiveness
by inducing matrix metalloproteinase-2 (MMP-2) and
urokinase-type plasminogen activator (uPA) expression
and activation in glioblastoma cells.26,50
Cancer Stem Cell Regulation
Illustrative of its multiple roles, MET has been shown
to contribute to glioma malignancy and resistance to antiproliferative therapies by regulating glioma stem cells
(GSCs). Several preclinical studies showed that MET is
highly expressed in GSCs.29,30,43 MET enhances GSCs via
inducing the expression of reprogramming transcription
factors and inducing differentiated cells to form multipotent stem cells.43 Additionally, MET pathway inhibition
in GSCs inhibits tumor growth and invasiveness both in
vivo and in vitro.29,56
Angiogenesis
The organization of endothelial cells into tubelike
structures is an essential step in blood vessel formation.
A study was conducted to analyze the capacity of angiogenic factors, including HGF, to induce endothelial tube
formation in collagen gels.59 It showed that tissue levels of
angiogenic factor extracts from high-grade gliomas were
significantly more potent than extracts from low-grade
tumors in stimulating endothelial cell tube formation. 59
Additionally, HGF concentrations correlate with glioma
grade and microvessel density, as determined by immunostaining for factor VIII–related antigen.59 Another
study found that endothelial tubulogenesis increased in
cocultures of endothelial cells and glioma tumor cells
that secrete angiogenic factors, including HGF, but not
with nontumorigenic cell types such as epithelial cells.34
A recent report showed that bevacizumab-resistant
GBMs display increased hypoxia compared with pretreatment tumors in a manner correlating with their MET
upregulation and activation. Moreover, silencing the MET
gene in bevacizumab-resistant GBM–derived xenografts
inhibited their invasion and survival in hypoxia, and converted them from bevacizumab resistant to bevacizumab
responsive.27
HGF and MET as Targets for Glioma Therapy
Because of its widespread and profound involvement
in human cancer, the MET pathway has emerged as an attractive target for cancer therapy. Among others, the following approaches have been developed to inhibit MET
and/or HGF.
U1snRNA/Ribozymes and Antisense
Gene therapy approaches were the first used to in3
A. J. Awad et al.
hibit HGF and MET expressions in experimental glioma
animal models. Chimeric U1snRNA/ribozyme transgenes were the first agents used to inhibit HGF and MET
expression in human cancer. Glioma xenografts were
treated with U1snRNA/ribozymes delivered via liposome-DNA complexes and adenoviruses.2,5 There was
marked tumor growth inhibition as well as tumor HGF
and lower MET expression levels. Additionally, histological analysis showed a significant increase in brain tumor
cell apoptosis and a significant decrease in tumor blood
vessel density in glioma tumor cells treated with U1snRNA/ribozymes. It was also shown that combining ionizing radiation therapy with U1snRNA/ribozyme achieves
synergistic effects on angiogenesis inhibition.36 MET
antisense oligonucleotides were also tested in glioma xenograft animal models. Antisense MET oligodeoxynucleotides enhanced the sensitivity of human glioma cells
to paclitaxel; cell growth inhibition and apoptosis were
more significantly affected than with either paclitaxel or
the oligodeoxynucleotides alone.16
NK4
NK4 is a synthetic molecule that comprises the NH2terminal hairpin domain and subsequent 4-kringle domains of HGF, but lacks the entire a chain. NK4 works
by competitively inhibiting the specific binding of HGF
to its receptor MET. In one study, mice bearing intracranial glioma xenografts received daily intratumoral injections of NK4 or buffer beginning 1–7 days after tumor
cell implantation. Tumor volumes were reduced by 61%
in the NK4-treated mice.13 The proliferative activity of
the tumor cells and intratumoral microvessel densities
were reduced by > 30% regardless of when NK4 treatment was initiated. Additionally, the apoptotic fraction of
tumor cells was increased up to 2-fold.13
Small-Molecule Inhibitors
Small-molecule kinase inhibitors are one of the most
promising classes of targeted therapeutics for interfering
with RTK pathway activation. These small molecules have
good bioavailability following systemic delivery and have
been clinically validated against many targets. There has
been a recent surge in the development of small-molecule
MET inhibitors, with at least 10 compounds in various
phases of development.17,25 ARQ197 [ArQule] is one example of a non-ATP–competitive MET-specific inhibitor
highly selective for the MET receptor. The half maximal
inhibitory concentration values for MET inhibition and
for multiple MET-driven cell responses are in the 50- to
100-nM range. ARQ197 is currently in Phase II and III
trials for various systemic cancers. Other small-molecule
inhibitors are somewhat less specific, but have the potential
to simultaneously target multiple oncogenic kinases relevant to brain cancers. Exelixis has generated cabozantinib
(XL-184), which inhibits both MET and VEGFR2. The
cabozantinib Phase II study for relapsed GBM reported
encouraging preliminary results. Of 26 patients assessed at
4 weeks, 10 patients (38%) achieved radiological response
of ≥ 50% reduction from baseline, and 9 patients (35%) had
tumor measurement reduction ranging from 24% to 49%.18
4
Neutralizing mAbs
Together with small-molecule inhibitors, mAbs presently constitute the most clinically applicable HGF/MET
pathway inhibitors. Monoclonal antibodies are very specific and have a long biological half-life. Additionally,
mAbs have the potential to chelate diffusible targets out
of the brain and tumor parenchyma despite blood-brain
barrier–associated limitations. Amgen, Inc. has generated and characterized several distinct, fully human mAbs,
each of which binds to an epitope in the b chain of HGF,
neutralizing it. One of these mAbs, rilotumumab (AMG
102), has already completed two Phase II clinical trials
for recurrent GBM. The first trial studied rilotumumab
alone,66 whereas the other studied the combination of rilotumumab with bevacizumab.6 In both trials, the overall survival was approximately 6 months. However, the
first trial did not find significant antitumor activity, and
the progression-free survival was similar among patients
who had previously received bevacizumab compared
with bevacizumab-naive patients.66
It has not been possible to inhibit MET by using bivalent anti-MET antibodies because antibody-mediated
receptor dimerization can induce receptor activation.
MetMAb (OA-5D5) is a novel one-armed (monovalent)
anti-MET antibody that has been developed to inhibit
MET activation and GBM xenograft growth.46 Infusing
the OA-5D5 anti-MET antibody directly into intracranial
tumor xenografts inhibited the growth of HGF+/MET+
U87MG gliomas without affecting HGF−/MET+ G55
gliomas, thereby demonstrating mechanistic specificity.
In OA-5D5–treated U87MG xenografts, cell proliferation and microvessel density were dramatically reduced,
and apoptosis was significantly increased.46 This study
demonstrated the feasibility and effectiveness of local intracranial delivery for brain tumor therapy. MetMAb has
been humanized and affinity-matured to generate onartuzumab, which is under Phase II trial for recurrent GBM.
Current Trials and Therapeutic Considerations
Currently, there are 9 registered trials targeting HGF
and MET in patients with gliomas. To date, these trials
are in Phase I–II stages. Table 1 shows a summary of
HGF and MET trials. Glioblastoma multiforme displays
a considerable histopathological and genetic heterogeneity. Due to this complexity, it is most likely that only a
subset of patients will benefit from HGF/MET pathway
inhibition. It is therefore important to identify the factors
that determine sensitivity to MET inhibition in GBM.
Two recent studies found that HGF coexpression is the
most important predictor of responsiveness to MET inhibition in animal models of GBM.68,69 Also, because of signal redundancy and compensatory mechanisms as well
as the involvement of multiple molecular pathways in the
growth, migration, invasion, and apoptotic resistance of
tumor cells, it is unlikely that single molecular therapies
would achieve substantial antitumor effects. Combination molecular therapies that simultaneously target different pathways are likely to achieve greater therapeutic
success. Basic and translational research has provided a
rationale for combining anti-HGF/MET therapies with
Neurosurg Focus / Volume 37 / December 2014
Targeting MET for glioma therapy
TABLE 1: Summary of clinical trials targeting the MET/HGF signaling pathway
Drug
Phase
Status
Patient Population
Combinations
Clinical Trial
—
NCT00427440
NCT01113398
NCT01632228
Rilotumumab (AMG 102)
Rilotumumab (AMG 102)
Onartuzumab (MetMAb)
II
II
II
completed
active
active, not recruiting
advanced malignant glioma
recurrent malignant glioma
recurrent GBM
Ficlatuzumab (AV-299)
Golvatinib (E7050)
I
I/II
withdrawn
active, not recruiting
INCB28060 (INC280)
Crizotinib (PF02341066)
Ib/II
I
recruiting
recruiting
Cabozantinib (XL-184)
Cabozantinib (XL-184)
II
I
completed
active, not recruiting
GBM
advanced solid malignancies,
GBM, unresectable Stage
III/IV melanoma
recurrent GBM
buparlisib
diffuse intrinsic pontine glioma, dasatinib
high-grade glioma, pediatric
GBM
—
GBM
temozolomide/radiation therapy
traditional cytotoxic therapies such as radiotherapy and
chemotherapy. Other recent research has provided the rationale for combining anti-MET therapies with other molecular therapies.1,40,57 However, more research is required
to uncover the interactions between MET and other oncogenic pathways in gliomas to devise new patient-tailored
and more efficient MET combination therapies.
Disclosure
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this
paper.
Author contributions to the study and manuscript preparation
include the following. Conception and design: Awad. Acquisition of
data: Awad. Analysis and interpretation of data: Awad. Drafting the
article: Awad. Critically revising the article: all authors. Reviewed
submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Abounader.
References
1. Abounader R: Interactions between PTEN and receptor tyrosine kinase pathways and their implications for glioma therapy. Expert Rev Anticancer Ther 9:235–245, 2009
2. Abounader R, Lal B, Luddy C, Koe G, Davidson B, Rosen
EM, et al: In vivo targeting of SF/HGF and c-met expression
via U1snRNA/ribozymes inhibits glioma growth and angiogenesis and promotes apoptosis. FASEB J 16:108–110, 2002
3. Abounader R, Laterra J: Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis. Neuro Oncol 7:
436–451, 2005
4. Abounader R, Ranganathan S, Kim BY, Nichols C, Laterra J:
Signaling pathways in the induction of c-met receptor expression by its ligand scatter factor/hepatocyte growth factor in
human glioblastoma. J Neurochem 76:1497–1508, 2001
5. Abounader R, Ranganathan S, Lal B, Fielding K, Book A, Dietz H, et al: Reversion of human glioblastoma malignancy by
U1 small nuclear RNA/ribozyme targeting of scatter factor/
hepatocyte growth factor and c-met expression. J Natl Cancer Inst 91:1548–1556, 1999
6. Affronti ML, Desjardins A, Friedman HS, Peters KB, Herndon JE II, McSherry F, et al: Phase II study to evaluate the efficacy and safety of rilotumumab and bevacizumab (BEV) in
Neurosurg Focus / Volume 37 / December 2014
bevacizumab
+ bevacizumab vs bevacizumab
alone vs MetMAb monotherapy,
randomized
—
lenvatinib
NCT01189513
NCT01433991
NCT01870726
NCT01644773
NCT00704288
NCT00960492
subjects with recurrent malignant glioma (MG). J Clin Oncol
30 Suppl:2074, 2012 (Abstract)
7. Arrieta O, Garcia E, Guevara P, Garcia-Navarrete R, Ondarza
R, Rembao D, et al: Hepatocyte growth factor is associated
with poor prognosis of malignant gliomas and is a predictor
for recurrence of meningioma. Cancer 94:3210–3218, 2002
8. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF:
Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:
915–925, 2003
9. Blume-Jensen P, Hunter T: Oncogenic kinase signalling. Nature 411:355–365, 2001
10. Boccaccio C, Andò M, Tamagnone L, Bardelli A, Michieli P,
Battistini C, et al: Induction of epithelial tubules by growth
factor HGF depends on the STAT pathway. Nature 391:285–
288, 1998
11. Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE,
Vande Woude GF, et al: Identification of the hepatocyte growth
factor receptor as the c-met proto-oncogene product. Science
251:802–804, 1991
12. Bowers DC, Fan S, Walter KA, Abounader R, Williams JA,
Rosen EM, et al: Scatter factor/hepatocyte growth factor
protects against cytotoxic death in human glioblastoma via
phosphatidylinositol 3-kinase- and AKT-dependent pathways.
Cancer Res 60:4277–4283, 2000
13. Brockmann MA, Papadimitriou A, Brandt M, Fillbrandt R,
Westphal M, Lamszus K: Inhibition of intracerebral glioblastoma growth by local treatment with the scatter factor/hepatocyte
growth factor-antagonist NK4. Clin Cancer Res 9:4578–4585,
2003
14. Brockmann MA, Ulbricht U, Grüner K, Fillbrandt R, Westphal M, Lamszus K: Glioblastoma and cerebral microvascular endothelial cell migration in response to tumor-associated
growth factors. Neurosurgery 52:1391–1399, 2003
15. Cancer Genome Atlas Research Network: Comprehensive genomic characterization defines human glioblastoma genes and
core pathways. Nature 455:1061–1068, 2008
16. Chu SH, Ma YB, Feng DF, Zhang H, Qiu JH, Zhu ZA: c-Met
antisense oligodeoxynucleotides increase sensitivity of human glioma cells to paclitaxel. Oncol Rep 24:189–194, 2010
17. Comoglio PM, Giordano S, Trusolino L: Drug development
of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov 7:504–516, 2008
18. De Groot JF, Prados M, Urquhart T, Robertson S, Yaron Y,
Sorensen AG, et al: A phase II study of XL184 in patients
(pts) with progressive glioblastoma multiforme (GBM) in first
or second relapse. ASCO Meeting Abstracts 27:2047, 2009
5
A. J. Awad et al.
19. Fan S, Ma YX, Gao M, Yuan RQ, Meng Q, Goldberg ID, et al:
The multisubstrate adapter Gab1 regulates hepatocyte growth
factor (scatter factor)-c-Met signaling for cell survival and
DNA repair. Mol Cell Biol 21:4968–4984, 2001
20. Fan S, Meng Q, Laterra JJ, Rosen EM: Ras effector pathways
modulate scatter factor-stimulated NF-kappaB signaling and
protection against DNA damage. Oncogene 26:4774–4796,
2007
21. Fuller GN, Ribalta T: Brain tumors: an overview of current
histopathologic classifications, in Winn HR (ed): Youmans
Neurological Surgery, ed 6. Philadelphia: Elsevier/Saunders,
2011, Vol 2, pp 1077–1086
22. Gherardi E, Youles ME, Miguel RN, Blundell TL, Iamele L,
Gough J, et al: Functional map and domain structure of MET,
the product of the c-met protooncogene and receptor for hepatocyte growth factor/scatter factor. Proc Natl Acad Sci U S A
100:12039–12044, 2003
23. Giordano S, Ponzetto C, Di Renzo MF, Cooper CS, Comoglio
PM: Tyrosine kinase receptor indistinguishable from the cmet protein. Nature 339:155–156, 1989
24. Gude NA, Emmanuel G, Wu W, Cottage CT, Fischer K, Quijada P, et al: Activation of Notch-mediated protective signaling in the myocardium. Circ Res 102:1025–1035, 2008
25. Guessous F, Zhang Y, diPierro C, Marcinkiewicz L, Sarkaria
J, Schiff D, et al: An orally bioavailable c-Met kinase inhibitor
potently inhibits brain tumor malignancy and growth. Anticancer Agents Med Chem 10:28–35, 2010
26. Hamasuna R, Kataoka H, Moriyama T, Itoh H, Seiki M, Koono M: Regulation of matrix metalloproteinase-2 (MMP-2)
by hepatocyte growth factor/scatter factor (HGF/SF) in human glioma cells: HGF/SF enhances MMP-2 expression and
activation accompanying up-regulation of membrane type-1
MMP. Int J Cancer 82:274–281, 1999
27. Jahangiri A, De Lay M, Miller LM, Carbonell WS, Hu YL,
Lu K, et al: Gene expression profile identifies tyrosine kinase
c-Met as a targetable mediator of antiangiogenic therapy resistance. Clin Cancer Res 19:1773–1783, 2013
28. Johnson DR, O’Neill BP: Glioblastoma survival in the United
States before and during the temozolomide era. J Neurooncol
107:359–364, 2012
29. Joo KM, Jin J, Kim E, Ho Kim K, Kim Y, Gu Kang B, et
al: MET signaling regulates glioblastoma stem cells. Cancer
Res 72:3828–3838, 2012
30. Kim KH, Seol HJ, Kim EH, Rheey J, Jin HJ, Lee Y, et al:
Wnt/b-catenin signaling is a key downstream mediator of
MET signaling in glioblastoma stem cells. Neuro Oncol 15:
161–171, 2013
31. Kim KJ, Wang L, Su YC, Gillespie GY, Salhotra A, Lal B,
et al: Systemic anti-hepatocyte growth factor monoclonal antibody therapy induces the regression of intracranial glioma
xenografts. Clin Cancer Res 12:1292–1298, 2006
32. Koochekpour S, Jeffers M, Rulong S, Taylor G, Klineberg E,
Hudson EA, et al: Met and hepatocyte growth factor/scatter
factor expression in human gliomas. Cancer Res 57:5391–
5398, 1997
33. Kunkel P, Müller S, Schirmacher P, Stavrou D, Fillbrandt R,
Westphal M, et al: Expression and localization of scatter factor/hepatocyte growth factor in human astrocytomas. Neuro
Oncol 3:82–88, 2001
34. Lafleur MA, Handsley MM, Knäuper V, Murphy G, Edwards
DR: Endothelial tubulogenesis within fibrin gels specifically
requires the activity of membrane-type-matrix metalloproteinases (MT-MMPs). J Cell Sci 115:3427–3438, 2002
35. Laisney JA, Mueller TD, Schartl M, Meierjohann S: Hyperactivation of constitutively dimerized oncogenic EGF receptors
by autocrine loops. Oncogene 32:2403–2411, 2013
36. Lal B, Xia S, Abounader R, Laterra J: Targeting the c-Met
pathway potentiates glioblastoma responses to gamma-radiation. Clin Cancer Res 11:4479–4486, 2005
6
37. Lamszus K, Laterra J, Westphal M, Rosen EM: Scatter factor/
hepatocyte growth factor (SF/HGF) content and function in
human gliomas. Int J Dev Neurosci 17:517–530, 1999
38. Lamszus K, Schmidt NO, Jin L, Laterra J, Zagzag D, Way D,
et al: Scatter factor promotes motility of human glioma and
neuromicrovascular endothelial cells. Int J Cancer 75:19–28,
1998
39. Laterra J, Nam M, Rosen E, Rao JS, Lamszus K, Goldberg
ID, et al: Scatter factor/hepatocyte growth factor gene transfer
enhances glioma growth and angiogenesis in vivo. Lab Invest
76:565–577, 1997
40. Li Y, Guessous F, DiPierro C, Zhang Y, Mudrick T, Fuller L,
et al: Interactions between PTEN and the c-Met pathway in
glioblastoma and implications for therapy. Mol Cancer Ther
8:376–385, 2009
41. Li Y, Guessous F, Johnson EB, Eberhart CG, Li XN, Shu Q, et
al: Functional and molecular interactions between the HGF/cMet pathway and c-Myc in large-cell medulloblastoma. Lab
Invest 88:98–111, 2008
42. Li Y, Lal B, Kwon S, Fan X, Saldanha U, Reznik TE, et al:
The scatter factor/hepatocyte growth factor: c-met pathway in
human embryonal central nervous system tumor malignancy.
Cancer Res 65:9355–9362, 2005
43. Li Y, Li A, Glas M, Lal B, Ying M, Sang Y, et al: c-Met signaling induces a reprogramming network and supports the
glioblastoma stem-like phenotype. Proc Natl Acad Sci U S A
108:9951–9956, 2011
44. Lock LS, Royal I, Naujokas MA, Park M: Identification of an
atypical Grb2 carboxyl-terminal SH3 domain binding site in
Gab docking proteins reveals Grb2-dependent and -independent recruitment of Gab1 to receptor tyrosine kinases. J Biol
Chem 275:31536–31545, 2000
45. Lokker NA, Sullivan CM, Hollenbach SJ, Israel MA, Giese
NA: Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma
cells: evidence that the novel PDGF-C and PDGF-D ligands
may play a role in the development of brain tumors. Cancer
Res 62:3729–3735, 2002
46. Martens T, Schmidt NO, Eckerich C, Fillbrandt R, Merchant
M, Schwall R, et al: A novel one-armed anti-c-Met antibody
inhibits glioblastoma growth in vivo. Clin Cancer Res 12:
6144–6152, 2006
47. Martínez-Rumayor A, Arrieta O, Guevara P, Escobar E, Rembao D, Salina C, et al: Coexpression of hepatocyte growth
factor/scatter factor (HGF/SF) and its receptor cMET predict
recurrence of meningiomas. Cancer Lett 213:117–124, 2004
48. Miyazawa K, Shimomura T, Kitamura A, Kondo J, Morimoto
Y, Kitamura N: Molecular cloning and sequence analysis of
the cDNA for a human serine protease responsible for activation of hepatocyte growth factor. Structural similarity of
the protease precursor to blood coagulation factor XII. J Biol
Chem 268:10024–10028, 1993
49. Monga SP, Mars WM, Pediaditakis P, Bell A, Mulé K, Bowen
WC, et al: Hepatocyte growth factor induces Wnt-independent
nuclear translocation of beta-catenin after Met-beta-catenin
dissociation in hepatocytes. Cancer Res 62:2064–2071, 2002
50. Moriyama T, Kataoka H, Hamasuna R, Yoshida E, Sameshima T, Iseda T, et al: Simultaneous up-regulation of urokinasetype plasminogen activator (uPA) and uPA receptor by hepatocyte growth factor/scatter factor in human glioma cells.
Clin Exp Metastasis 17:873–879, 1999
51. Moriyama T, Kataoka H, Kawano H, Yokogami K, Nakano S,
Goya T, et al: Comparative analysis of expression of hepatocyte
growth factor and its receptor, c-met, in gliomas, meningiomas
and schwannomas in humans. Cancer Lett 124:149–155, 1998
52. Nakagami H, Morishita R, Yamamoto K, Taniyama Y, Aoki
M, Matsumoto K, et al: Mitogenic and antiapoptotic actions of
hepatocyte growth factor through ERK, STAT3, and AKT in
endothelial cells. Hypertension 37:581–586, 2001
Neurosurg Focus / Volume 37 / December 2014
Targeting MET for glioma therapy
53. Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M,
Sugimura A, et al: Molecular cloning and expression of human hepatocyte growth factor. Nature 342:440–443, 1989
54. Ohgaki H: Epidemiology of brain tumors. Methods Mol Biol
472:323–342, 2009
55. Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, et al: A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell 77:261–271, 1994
56. Rath P, Lal B, Ajala O, Li Y, Xia S, Kim J, et al: In vivo cMet pathway inhibition depletes human glioma xenografts of
tumor-propagating stem-like cells. Transl Oncol 6:104–111,
2013
57. Reznik TE, Sang Y, Ma Y, Abounader R, Rosen EM, Xia S,
et al: Transcription-dependent epidermal growth factor receptor activation by hepatocyte growth factor. Mol Cancer Res
6:139–150, 2008
58. Rosen EM, Laterra J, Joseph A, Jin L, Fuchs A, Way D, et
al: Scatter factor expression and regulation in human glial tumors. Int J Cancer 67:248–255, 1996
59. Schmidt NO, Westphal M, Hagel C, Ergün S, Stavrou D, Rosen
EM, et al: Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth
factor in human gliomas and their relation to angiogenesis. Int
J Cancer 84:10–18, 1999
60. Seki T, Hagiya M, Shimonishi M, Nakamura T, Shimizu S:
Organization of the human hepatocyte growth factor-encoding gene. Gene 102:213–219, 1991
61. Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, et al: Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted
therapies. Science 318:287–290, 2007
62. Vlahovic G, Crawford J: Activation of tyrosine kinases in cancer. Oncologist 8:531–538, 2003
63. Walter KA, Hossain MA, Luddy C, Goel N, Reznik TE, Laterra J: Scatter factor/hepatocyte growth factor stimulation of
glioblastoma cell cycle progression through G(1) is c-Myc dependent and independent of p27 suppression, Cdk2 activation,
Neurosurg Focus / Volume 37 / December 2014
or E2F1-dependent transcription. Mol Cell Biol 22:2703–
2715, 2002
64. Weidner KM, Di Cesare S, Sachs M, Brinkmann V, Behrens J,
Birchmeier W: Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature 384:173–176, 1996
65. Welch WC, Kornblith PL, Michalopoulos GK, Petersen BE,
Beedle A, Gollin SM, et al: Hepatocyte growth factor (HGF)
and receptor (c-met) in normal and malignant astrocytic cells.
Anticancer Res 19 (3A):1635–1640, 1999
66. Wen PY, Schiff D, Cloughesy TF, Raizer JJ, Laterra J, Smitt
M, et al: A phase II study evaluating the efficacy and safety of
AMG 102 (rilotumumab) in patients with recurrent glioblastoma. Neuro Oncol 13:437–446, 2011
67. Xiao GH, Jeffers M, Bellacosa A, Mitsuuchi Y, Vande Woude
GF, Testa JR: Anti-apoptotic signaling by hepatocyte growth
factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. Proc Natl Acad Sci
U S A 98:247–252, 2001
68. Xie Q, Bradley R, Kang L, Koeman J, Ascierto ML, Worschech A, et al: Hepatocyte growth factor (HGF) autocrine
activation predicts sensitivity to MET inhibition in glioblastoma. Proc Natl Acad Sci U S A 109:570–575, 2012
69. Zhang Y, Farenholtz KE, Yang Y, Guessous F, Dipierro CG,
Calvert VS, et al: Hepatocyte growth factor sensitizes brain
tumors to c-MET kinase inhibition. Clin Cancer Res 19:
1433–1444, 2013
Manuscript submitted August 15, 2014.
Accepted September 23, 2014.
Please include this information when citing this paper: DOI:
10.3171/2014.9.FOCUS14520.
Address correspondence to: Roger Abounader, M.D., Ph.D.,
De­partment of Microbiology, Immunology, and Cancer Biology,
Uni­­versity of Virginia, Box 800168, Charlottesville, VA 22908.
email: [email protected].
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