Response to imatinib as a function of target kinase expression in recurrent glioblastoma

Abstract

Despite some progress in the treatment of glioblastoma, most patients experience tumor recurrence. Imatinib mesylate, a tyrosine kinase inhibitor of platelet derived growth factor receptor-alpha and -beta, c-fms, c-kit, abl and arg kinase (imatinib targets), has been shown to prevent tumor progression in early studies of recurrent gliomas, but has shown weak activity in randomized controlled trials. We studied the response to oral imatinib in 24 patients with recurrent glioblastoma who showed immunohistochemical expression of these imatinib targets in the initially resected tumor tissue.
We offered oral imatinib, 400 mg once daily treatment to 24 recurrent glioblastoma patients whose initial biopsy showed presence of at least one imatinib inhibitable tyrosine kinase.
Six imatinib treated patients survived over one year. Twelve patients achieved at least tumor stabilisations from 2.6 months to 13.4 months. Median progression free survival was 3 months and median overall survival was 6 months. Imatinib was well tolerated. We found evidence, though not statistically significant, that arg kinase [Abl-2] immunopositivity had shorter survival [5 months] than the arg kinase immunonegative group [9 months].
Responses to imatinib observed in this patient series where imatinib inhibitable tyrosine kinases were documented on the original biopsy are marginally better than that previously reported in imatinib treatment of unselected recurrent glioblastoma patients. We thus present a suggestion for defining a patient sub-population who might potentially benefit from imatinib.

Full text

SHO R T REP O R T Open Access
Response to imatinib as a function of target
kinase expression in recurrent glioblastoma
Marco Ronald Hassler
1
, Mariam Vedadinejad
1
, Birgit Flechl
1
, Christine Haberler
2
, Matthias Preusser
1
,
Johannes Andreas Hainfellner
2
, Adelheid Wöhrer
2
, Karin Ute Dieckmann
3
, Karl Rössler
4
, Richard Kast
1
and Christine Marosi
1,5*
Abstract
Background: Despite some progress in the treatment of glioblastoma, most patients experience tumor recurrence.
Imatinib mesylate, a tyrosine kinase inhibitor of platelet derived growth factor receptor-alpha and -beta, c-fms, c-kit,
abl and arg kinase (imatinib targets), has been shown to prevent tumor progression in early studies of recurrent
gliomas, but has shown weak activity in randomized controlled trials. We studied the response to oral imatinib in
24 patients with recurrent glioblastoma who showed immunohistochemical expression of these imatinib targets in
the initially resected tumor tissue.
Methods: We offered oral imatinib, 400 mg once daily treatment to 24 recurrent glioblastoma patients whose
initial biopsy showed presence of at least one imatinib inhibitable tyrosine kinase.
Results: Six imatinib treated patients survived over one year. Twelve patients achieved at least tumor stabilisations
from 2.6 months to 13.4 months. Median progression free survival was 3 months and median overall survival was
6 months. Imatinib was well tolerated. We found evidence, though not statistically significant, that arg kinase [Abl-2]
immunopositivity had shorter survival [5 months] than the arg kinase immunonegative group [9 months].
Conclusions: Responses to imatinib observed in this patient series where imatinib inhibitable tyrosine kinases were
documented on the original biopsy are marginally better than that previously reported in imatinib treatment of
unselected recurrent glioblastoma patients. We thus present a suggestion for defining a patient sub-population
who might potentially benefit from imatinib.
Keywords: c-Abl; Arg kinase; c-Fms; c-kit; Cytokine; Glioblastoma; Inatinib; Markers; Platelet derived growth factor;
Tyrosine kinase
Introduction
Over the last ten years overall sur vival (OS) in glioblast-
oma (GB) after initial surgery has improved somewhat.
After diagnosis of GB standard therapy consists in max-
imal feasible resection, followed by radiotherapy and con-
comitant adjuvant therapy with temozolomide (TMZ)
(Stupp et al. 2009; Minniti et al. 2008; Taphoorn and
Bottomley 2005), applicable also in older patients (Minniti
et al. 2008) albeit resulting in shorter OS than in younger
cohorts. This approach has led to an improved overall
survival (OS) rate from 11 months to 15 to 20 months
currently (Stupp et al. 2009; Minniti et al. 2008; Taphoorn
and Bottomley 2005; Wöhrer et al. 2009). Clearly more is
needed.
Almost all patients develop recurrences within two
years after diagnosis. There is no current standard or
established treatment for recurrent GB. Increasingly we
are seeing patients with recurrent GB that are in better
clinical condition than we saw ten years ago and who
wish for and could tolerate additions to Treatment
Options.
At re currence, for each patient there are important in-
dividual treatment decisions depending on: i) clinical
condition, ii) localisation of recurrence that determines
* Correspondence: christine.marosi@meduniwien.ac.at
1
Department of Internal Medicine I, Clinical Division of Oncology, 1-3
Comprehensive Cancer Center-Central Nervous System Tumors Unit
(CCC-CNS), Medical University of Vienna, Vienna, Austria
5
Department of Internal Medicine I, Clinical Division of Oncology, Währinger
Gürtel 18-20, Vienna 1090, Austria
Full list of author information is available at the end of the article
a SpringerOpen Journal
© 2014 Hassler et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction
in any medium, provided the original work is properly credited.
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suitab ility for seco nd resection, iii) time e lapsed since
initial treatment to determine potential usefulness of re-
irradiatio n, iv) methylation status of the methyl guanine
methyl transferase (MGMT) gene promoter, v) potential
for inclusion of the patient in an investigational treat-
ment trial, and perhaps most importantly, vi) patient
preference for t he various risk-benefit options.
One of the first tyrosine kinase (TK) inhibitors tested
in re current GB was imatinib (Gleevec® or Glivec®) (Wen
et al. 2006). For an excellent review of imatinib’s devel-
opment, kinase inhibition attributes, mechanism of ac-
tion, and early clinical results, see ref. (Waller 2010).
Imatinib inhibits several important TK ’s that have been
shown to be active in promoting GB growth such as plate-
let derived growth factor receptor (PDGFR) -α and -β
(George 2003), c-Abl kinase (Panjarian et al. 2013), c-kit
(Lennartsson and Ronnstrand 2012), arg (Mader et al.
2011; Beaty et al. 2013), and c-Fms, (Mouchemore and
Pixley 2012). c-Abl kinase is a non-receptor TK where
cytoplasmic activity is cell survival promoting yet nuclear
activity is cell death promoting (Panjarian et al. 2013).
c-kit, synonymous with CD117, is an outer cell-surface
tyrosine kinase transmembrane receptor for 18 kDa stem
cell factor (Lennartsson and Ronnstrand 2012), and c-fms
is a cell surface receptor for 108 kDa colony stimulating
factor-1, also known as macrophage-colony stimulating
factor (Mouchemore and Pixley 2012). arg is the Abelson-
related gene product, (same as Abl-related nonreceptor
tyrosine kina se Arg , or Abl2), a large nonreceptor TK
(Mader et al. 2011; Beaty et al. 2013). Of particular note
arg, although commonly seen to be an element promot-
ing cancer cell invasion [as in breast cancer 10, 11], can
in some cancers work to arrest invasion (Hayes et al.
2012). We outline below results that could indicate GB
might be another such cancer, complicating the use o f
imatinib.
Focal expression of PDGFR-alpha protein occurs in
25% of unselected GB’s, PGFR-beta in 19%, c-kit in 4%,
and c-abl in 7% (Haberler et al. 2006). c-fms is expressed
in glioblastoma but to what degree or frequency hasn’t
been determined (Alterman and Stanley 1994).
Initial enthusiasm for imatinib was based on robust pre-
clinical evidence (Wen et al. 2006; Waller 2010; Morris
and Abrey 2010) but subsequent weakness of imatinib in
clinical trials in unselected recurrent GB has since damp-
ened enthusiasm. In single agent studies, both using
400 mg p.o. twice daily, Raymond et al. found imatinib
gave a 16% progression free survival at six months
(Raymond et al. 2008) while Wen et al. found a 10% pro-
gression free survival at six months (Wen et al. 2006). Yet
two independent studies documented good GB tissue
levels of imatinib and its primary active metabolite, ap-
proximately equal to or in some cases greater than blood
levels (Razis et al. 2009; Holdhoff et al. 2010). This high
tumor tissue imatinib level was concordant with previous
murine studies (Tan et al. 2011; Soo et al. 2010).
Histologically glioblastoma has been traditionally diag-
nosed by presence of nuclear atypia, focal necrosis, florid
microvascular proliferation, and frequent mitotic figures.
Examination of mRNA expression patterns now allows
division of GB into molecular genetic subtypes, 1) pro-
neural, 2) neural, 3) classic, and 4) mesenchymal (Dunn
et al. 2012; Verhaak et al. 2010). The proneural subtype
consists of glioblastomas harbouring TP53 mutations
occurring mostly in younger patients and commonly
found together with isocitrate dehydrogenase (IDH) muta-
tion and PDFGR-alpha overexpression (Dunn et al. 2012;
Verhaak et al. 2010). We speculated that proneural sub-
type would preferentially benefit from imatinib by virtue
of having relatively higher dependence on dysregulated
imatinib targets. As the percentage of proneural GBM is
in the range of 12%, this could explain why the percentage
of patients responding to imatinib in unselected series is
remains low.
Based on in vitro data and on favourable clinical experi-
ence gained on Viennese patients participating in the
EORTC study 16011 [clinicaltrials.gov] and some add-
itional patients with advanced brain tumors treated with
imatinib on a compassionate use basis, we offered imatinib
to recurrent GB patients who were no longer candidates
for alkylating therapies and who had positive immunohis-
tochemical staining of PDGFR-α,or-β, or c-Abl, or c-kit,
or c-fms. We report here on these patients with recurrent
GB treated with imatinib.
Patients and methods
Patient eligibility
Entry requirements were recurrent GB, recurrent during
or shortly after treatment with alkylating agents equal or
less than three months after initial treatment ended and
who had tissue available for immunohistochemistry. Of
note, the analysis of the promoter methylation of the
gene methylguanine-methytransferase (MGMT) wa s not
done at our centre. Imatinib was offered only when pri-
mary resection tissue was positive on immunohistochem-
istry for one or more of the imatininb targets- PDGF-R α
or -β, c-abl, c-kit, arg, c-fms.
GB recurrence had to be diagnosed on recent contrast
enhanced magnetic resonance imaging scan (MRI). Pa-
tients were required to have no neurosurgical and or
radiotherapeutic option. They had to be aged 18 years or
older with a performance status ≤ 2 WHO score. Pa-
tients needed to have recovered from all toxicities from
previous therapies, to present with stable or decreasing
doses of corticosteroids for at least one week before start
of therapy an d to have adequate bone marrow, hepatic
and renal function (leukocyte count > 3,000/μL and a
platelet count > 100,000/μL; AL AT, ASAT, and alkaline
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phosphatase levels < two times upper limit of normal;
bilirubin, blood urea nitrogen and creatinine levels < 1.5
times of institutional normal levels).
Study design
This was an open label single centre named patient
study. There was no limit on the number of prior the r-
apies or number of previous tumor progressions. The
primary endpoint wa s survival duration after treatment
start with imatinib (OS), secondary endpoints were pro-
gression free survival (PFS) and the rate of PFS after
6 months of imatinib (PFS-6) and safety. The protocol
was reviewed and approved by the IRB of the Medical
University of Vienna, Austria.
Treatment intervention
Imatinib was given at 400 mg fixed dose per day on a con-
tinuous oral dosing schedule until tumor progression, un-
acceptable toxicity, or consent withdrawal occurred. We
did not have the opportunity to enhance the dosage of
imatinib in patients under enzyme inducing antiepileptic
drugs (EIAEDs), as there was no reimbursement for in-
creased doses. After the third patient, all further patients
were also given the proton pump inhibitor pantoprazol,
40 mg. in the morning, in order to minimize gastro-
intestinal side effects.
Treatment evaluation
Toxicity was evaluated according to the National Cancer
Institute (NCI) common toxicity criteria (CTC) 4.0
(Franklin et al. 1994; Trotti et al. 2003) during routine
monthly meetings, or at any time point when clinically
indicated. Safety assessments including monitoring of
serum chemistry and blood cell counts were done in bi-
weekly intervals at therapy start, extended to monthly
intervals after the first month.
Patients were monitored for treatment response with
clinical evaluation at monthly inter vals and every three
months with contrast enhanced MRI scans. Response
evaluation was based on MacDonald’s criteria (Macdonald
et al. 1990).
Immunohistochemistry
Immunohistochemical expression of PDGFR-α,-β,c-kit,
c-abl and arg was determined in paraffin-embedded tumor
specimens, fixed in 4% buffered formalin, as described
previously (Haberler et al. 2006). The following antibodies
were used at the indicated dilutions: polyclonal rabbit
anti-PDGFR-α antibody (sc-338, Santa Cruz Biotechnol-
ogy, Inc; 1:500), polyclonal rabbit anti-PDGFR-β antibody
(sc-339, Santa Cruz Biotechnology, Inc; 1:500), polyclonal
rabbit anti-human c-kit antibody (A4502, Dako, Glostrup
Denmark; 1:400), polyclonal rabbit anti-c-abl antibody
(sc-887, Santa Cruz Biotechnology, Inc; 1:1000) and
polyclonal goat anti-arg antibody (sc-6356, Santa Cruz
Biotechnology, Inc; 1:50). Additionally, phosphorylated
epitopes of PDGFR-α,-β, c-kit and abl were analyzed
using a polyclonal rabbit anti-PDGFR-α antibody (sc-
12910, Santa Cruz Biotechnology, Inc; 1.50), a monoclonal
mouse anti- PDGFR-β antibody (#3166, Cell Signalling
Technology, Inc; 1:20) a polyclonal rabbit anti-c-kit anti-
body (#3991, Cell Signalling Technology, Inc; 1:25), and a
polyclonal rabbit anti-c-abl antibody (#2864, Cell Signal-
ling Technology, Inc; 1:250).
Assessment of PDGFR-α,-β, c-kit, c-abl and arg expres-
sion pattern was done semi-quantitatively and scored as
widespread (>50%), moderate (50–10%), scant (<10%), or
negative labelling of tumor cells. Only tumor cells with
an intense ce ll-membrane-bound and/or intracytoplas-
mic immunoreac tivity were evaluated a s positive. A very
faint, smudgy or nuclear staining wa s not considered as
positive.
IDH1 mutation
Formalin-fixed and paraffin-embedded tumor tissue blocks
were cut at a thickness of 3-4 microns. Sections unde rwent
heat-induced antigen retrieval for 60 minutes and incu-
bated with the monoclonal IDH1-R132H antibody (clone
DIA-H09, Dianova, Hamburg, Germany) at a dilution of
1:30 for 60 minutes. Detection of immunolabelling was
performedusingtheFlex+Mousesystem(Dako,Glostrup,
Denmark) with diaminobenzidin as chromogen. Presence
or absence of tumor cell immunolabelling was evaluated
by one observer (A.W.). No case with partly positive and
partly negative staining of tumor cells was encountered.
Statistical considerations
The primary objective was to evaluate duration of sur-
vival of patients whose tumors had a positive staining
with “imatinib targets” at the initial diagnosis of glioma
from the day of starting imatinib 400 mg per day to the
day of death (OS), further, the duration of diagnosis of
tumor progression by imaging or the first day of clinical
deterioration associated with tumor progression or un-
explained death for any cause (PFS). Furthermore, the
rate of 6-month progression free survival and the dur-
ation of overall survival were calculated using the Kaplan
Meier method.
Results
Patient characteristics
Twenty-four patients fulfillin g eligibility criteria were
treated with imatinib. Average age was 53 years , with
male to female ratio of 13:11. Eleven patients received
imatinib as 2
nd
; nine patients as 3
rd
line therapy; two
patients a s 4
th
and two patients as 5
th
line therapy. Pa-
tients’ characteristics are summarized in Table 1.
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Patients started imatinib at a median 10.5 month s after
the first diagnosis, and after treatment with at least one
alkylating compound. The median duration of therapy
with imatinib was 3 months. Six of the 24 patients sur-
vived, and were treated for a year or more.
Toxicity
Side effects of imatinib therapy consisted in transient per-
ipheral oedema of legs or eye lids in six patients (25%),
mainly occurring shortly after start of therapy or concomi-
tantly to minor infections, i.e. of urinary tract. After com-
plaints of three patients about abdominal pain, we started
prescribing proton pump inhibitors to all patients and
these effects were not reported any longer. Nausea and
vertigo were reported by one patient each. No side effects
exceed CTC grade 2 and were mainly of transient charac-
ter. No patient had to stop imatinib because of toxicity
and none withdrew consent.
Immunohistochemistry
Table 2 lists the frequencies of expression of imatinib tar-
gets according to our semiquantitative scoring system.
Tumor tissue for all the mentioned immunohistochemical
analysis was available in 23/24 patients. In a patient with a
small biopsy only, not all analyses could be performed.
None of the 24 recurrent GB patients expressed c-kit.
IDH1 mutation was tested in 19/24 patients and positive
in only three.
Treatment outcome
Two patients achieved PR; one of them (nr.23 Table 2)
was a women aged 61 years at initial diagnosis of glio-
blastoma with 4 cm diameter in the right frontal lobe
that underwent a partial resection and later standard al-
kylating therapy (at this time with CCNU for 8 cycles of
42 days) and survived without progression until 35 months
after initial diagnosis. In addition, her tumor showed an
IDH1 mutation.
The other patient, a young, female patient aged 32y (nr
24 Table 2) was diagnosed with a more than 5 cm in diam-
eter left frontal GBM, underwent biopsy only followed by
concomitant and adjuvant therapy with Fotemustine/
Dacarbacine (8 cycles). Three months later her MRI scan
showed an increasing contrast enhancement (7 months
after Initial diagnosis) and she received one cycle of
Temozolomide 150 mg days 1–5 and because of severe
pancytopenia and expression of imatinib targets was then
given Imatinib. By retrospect, the increa sing contra st en-
hancing ma ss could have been pseudoprogression; but it
remains exceptiona l that she survived without any p ro-
gression for more than 60 months after a single adju-
vant cycle of temozolomide .
Ten additional patients reached stable disease, seven for
more than 6 months and up to thirteen months. Twelve
patients (50%) showed progressive disease at the first scan.
The median overall survival after the start of imatinib was
6.2 months and the median duration of PFS was three
months (see Figures 1 and 2). Patients responding to ima-
tinib showed rapid clinical improvement with subjective
relief of symptoms within two weeks and objective regres-
sion of contrast enhancing lesions in MRI, as shown for
one of the patients with major response (Figure 3).
We found no correlation between numbers of imatinib
targets positive, or with the percentage of immunohisto-
chemical staining cells for a given target and OS. Aver-
age number of targets positive, 3, was the same for the
11 patients with OS <6 months as the 13 patients with
OS > 6 months. We found no particular pattern of ima-
tinib targets positive or negative that predicted longer
OS other than arg, where negative staining predicted a
slightly longer OS (9 months in 14 patients) than immu-
nopositive patients (5 months in 9 patients).
Discussion
In this series we treated 24 glioblastoma patients with early
recurrence that had immunohistochemical expression of
Table 1 Patient characteristics
Primary GBM 24 (100%)
Sex – n (%)
Female 11 (45%)
Male 13 (55%)
Age – yr
Median (Range) 53 (18 – 72y)
Performance score – n (%)
WHO 0 0
WHO I 16 (65%)
WHO II 8 (33%)
Extent of surgery – n (%)
Biopsy 3 (12.5%)
Partial resection 11 (46%)
Gross total resection 10 (41.5%)
Previous chemotherapies
1 11 (46%)
2 9 (36%)
3 2 (3.5%)
4 2 (3.5%)
Antiepileptic drugs
None 10 (41.5%)
EIAEDs 10 (41.5%)
Non-EIAEDs 4 (18%)
GBM - glioblastoma multiforme.
EIAEDs - enzyme inducing antiepileptic drugs.
n - Number of patients.
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Table 2 Immunohistochemical markers and response to imatinib therapy
Pat. no. Sex Age (y) Delay to Th
start (m)
Th duration
(m)
Best response PFS m Survival m Arg pabl abl Pc-kit c-kit pPDGFR-β PDGFR-β PDGFR-α pPDGFR-α IDH-Ak
1 m 18,2 6,8 3 PD 3 6,2 neg <10% <10% <10% neg neg neg 10–50% <10% +
2 m 27,4 6,4 2,5 PD 2,5 2,5 neg neg neg neg neg neg neg <10% <10% -
3 f 59,4 4,5 1,6 PD 1.6 3,2 <10% neg neg neg neg neg neg <10% <10% -
4 m 48,5 5,4 1,7 PD 1,7 1,7 <10% neg <10% neg neg neg neg neg <10% -
5 f 49,8 13 1 PD 1 1 neg neg neg neg neg neg neg <10% n.a. -
6 m 60,9 25,1 0,6 PD 0.6 1,7 <10% 10–50% 10–50% <10% neg <10% neg <10% <10% +
7 m 50,5 15,6 0,8 PD 0,8 2,1 neg neg neg <10% neg neg neg neg Neg -
8 m 63,4 7,5 2 PD 2 11,7 <10% neg neg <10% neg <10% <10% <10% <10% na
9 m 56,1 4,7 1,5 PD 1,4 3,3 <10% neg <10% neg neg neg neg <10% <10% -
10 m 56,1 17,6 0,8 PD 0,8 0,8 <10% neg neg 10–50% neg >50% neg >50% >50% -
11 f 71,6 1 1,8 PD 1,8 1,8 neg neg neg <10% neg neg neg 10–50% 10–50% na
12 f 39 24,7 1,1 PD 1,1 1,1 <10% <10% <10% neg neg neg neg <10% <10% -
13 m 62,6 20,8 0,9 SD > 6m 7,9 17,1 neg neg neg <10% neg <10% neg neg <10% -
14 f 41 8,5 5,9 SD < 6m 5,9 10,4 neg neg neg 10–50% neg neg neg <10% 10–50% -
15 f 42,2 20 2,2 SD < 6m 2,6 4,6 neg neg neg neg neg neg neg <10% <10% -
16 m 56,9 4,3 5,8 SD < 6m 5,8 16,6 neg neg neg neg neg neg neg <10% 10–50% -
17 m 70,2 4,3 5,6 SD > 6m 5.6 13,4 neg 10–50% 10–50% <10% neg neg neg <10% >50% -
18 f 67 19,6 13,1 SD > 6m 13,1 13,1 10–50% neg neg <10% neg <10% neg 10–50% >50% na
19 f 62 4,3 8,1 SD > 6m 8,1 8,1 <10% 10–50% neg neg neg neg neg neg Neg na
20 f 48,6 4,4 6,2 SD > 6m 6,2 6,2 n.a. n.a. n.a. n.a. neg. <10% n.a. <10% n.a. na
21 m 59,5 8,8 8,9 SD > 6m 8,9 8,9 neg neg neg neg neg neg neg <10% Neg -
22 m 68,4 12,2 9,4 SD > 6m 9,4 9,4 neg <10% <10% neg neg neg neg <10% <10% -
23 f 32,1 14,5 7,3 PR 60 60 neg neg neg neg neg neg neg <10% <10% +
24 f 61,6 35,7 14,4 PR 14,4 32 neg neg neg neg neg <10% neg <10% Neg -
GBM - glioblastoma multiforme.
PD - progressive disease.
SD - stable disease < and > 6 months.
PR - partial response.
PFS - progression free survival after start of imatinib.
Survival: duration in months after start of imatinib.
m: months.
p: antibody against the phosphorylated form of a tyrosine kinase.
“<10%”: fewer than 10% of tumor cells expressed marker.
“neg”: assay was done and no reactive cells were found.
n.e.: not evaluable for response.
pt. 15: therapy stopped due to toxicities: ooedema, therapy stopped after 4 weeks.
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Figure 1 Kaplan Meier plot showing duration of progressive free survival from the start of imatinib to progression of GBM in
24 patients.
Figure 2 Kaplan Meier plot showing overall survival in patients with GBM from start of imatinib.
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imatinib targets in the initial tum or biopsy. We observed
marginally better results than that reported in previous
series of monotherapy with imatinib, Raymond et al. (giv-
ing 400 mg twice daily) saw 5.2 months OS compared to
our 6.2 (Raymond et al. 2008). Wen et al. saw 5.2 month
overall a vera ge, 3.1 month median PFS, 3% (1/33 patients)
progression free at 6 months compared to our 33% (8/24)
(Wen et al. 2006).
A
B
CD
Figure 3 MRI slides of patient with major response. T1 weighted, contrast enhanced MRT. A: Horizontal: before start of imatinib: with a left
frontal lesion with contrast enhancement. B: Horizontal: 3 months after start of imatinib, contrast enhancement of the lesion is not longer visible.
C: coronal, before start of imatinib with the contrast enhancing lesion near the ventricle. D: coronal, 3 months after start of imatinib: no contrast
enhancing lesion visible. The best fitted sections were selected for this image, as the head positioning and bending of the neck were not exactly
similar in both examinations.
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We saw 6/24 patients surviving more than one year
but were unable to identify any global TK pattern that
differentiated them from the 7/24 surviving less than
two months. However we did see a potentially interesting
OS of 9 months in patients whose biopsy immunostained
negative for the kinase arg (see Table 2) compared to OS
of 5 months for those staining positive, but this did not
reach significance. Furthermore within this study we were
not able to assess whether the chosen targets were overex-
pressed or amplified, nor their potential action on down-
stream targets.
However, we consider the possibility that GB is one of
the cancers where arg kinase activity inhibits invadopo-
dia activity similarly as found in head and neck cancers
(Hayes et al. 2012) and therefore whose inhibition would
be undesirable. A follow up study will exclude patient s
with positive arg biopsies from imatinib treatment in case
this association is not ephemeral. Our numbers were too
small to statistically exclude or confirm such association.
The toxicity related to imatinib intake was generally
low. Of note, neither clinically significant cytopenias, hep-
atic toxicity, nor cardiotoxicity were observed. This might
be due to the fact that most of the glioma patients are
using imatinib for shorter periods than would be typical in
patients with chronic myeloid leukemia. We also saw less
cytopenias than previous imatinib studies, perhaps due to
our use of 400 mg per day as opposed to 400 mg twice
daily in previous studies (Wen et al. 2006; Raymond et al.
2008). In this regard the potential for hormesis (Cox 2006;
Calabrese 2012) must be considered. Although we intui-
tively think of “more drug = greater effect” this does not
always hold. Hormesis- the U shaped [or inverted U
shaped curve] dose–response curve is not rare where in-
creasing dose after a given point can decrease total cyto-
toxicity, as with ciprofloxacin in vitro (Hincal et al. 2003).
Thus the lower dose we used compared to the previous
studies of (Wen et al. 2006) and (Raymond et al. 2008)
could account for better effect were hormesis to be active
in this dose range.
Randomized prospective trials are needed to confirm
this finding. Even if such trials confirm the small benefit
we saw, clearly augmentation strategies will be needed
for imatinib. To this end Soo et al. demonstrated three
fold increase in brain imatinib levels if co-administered
with the anti-malaria drug primaquine (Soo et al. 2010),
Tan et al. found 3.9 times the brain imatinib levels in mice
co-administered the anti-a naerobic antibiotic metronida-
zole (Tan et al. 2011). Since both metronidazole and prima-
quine are well-tolerated drugs with which we have decades
of experience, these might be easy ways to augment imati-
nib’s therapeutic index in treating GB. On the other hand if
hormesis is demonstrated such increased brain tissue levels
could be counterproductive. Only further research can
resolve this matter.
A facinating study by Coniglio et al. showed that c-
fms, an imatinib inhibitable TK , secreted by GB cells
strongly enhanced otherwise normal brain microglia’s in-
filtration into the growing tumor as well as the concomi-
tant centrifugal counter-migration of glioblastoma cells
(Coniglio et al. 2012 ). Epidermal grow th factor re ceptor
(EGFR , also termed HER-1) stimulation enhanced glio-
blastoma cells’ countermigration into surrou nding brain
[34], suggestin g that the EGFR inhibitor erlotinib may
be synergistic with imatinib i n su ppressing gliobla stoma
growth.
The high degree of spatial localization of over-expression
of PDGFRs makes sampling error risk high (Szerlip et al.
2012). The larger the t umor tissue we have to examine
the more reliable will be the determination of TK ex-
pression pattern. In confirming the tremendous hetero-
geneity within an i ndividual gliobla stoma, Little et al.
found to some degree that area s of EGFR and area s of
PDGFR overexpression tended to be mut ually exclusive
in human GB biopsy tissue (Little et al. 2012), again in-
dicating potential for erlotinib to increase imatinib’s
effectiveness.
Conclusion
We show ed marginal benefit of imatini b treatment of
recurrent glioblastomas expressing imatinib inhibitable
TKs. Our results were somewhat better than that found
in previous stud ies of unselected patients. We offer sev-
eral paths that might enhance imatinib effectiveness.
Abbreviations
BBB: Blood brain barrier; MGMT: Methyl guanine methyl transferase;
OS: Overall survival; PDGFR: Platelet derived growth factor receptor;
PFS: Progression free survival; QOL: Quality of life; TK: Tyrosine kinase.
Competing interest
The authors have no conflicts of interest.
Authors’ contribution
MRH and CM participated in making the concept and writing; MV, MP, KUD
and KR in reading; BF in patient reportings and reading; CH and JAH in
histological reportings; AW in histological reportings and writing; RK in
writing. All authors read and approved the final manuscript.
Author details
1
Department of Internal Medicine I, Clinical Division of Oncology, 1-3
Comprehensive Cancer Center-Central Nervous System Tumors Unit
(CCC-CNS), Medical University of Vienna, Vienna, Austria.
2
Institute of
Neurology, 1-3 Comprehensive Cancer Center-Central Nervous System
Tumors Unit (CCC-CNS), Medical University of Vienna, Vienna, Austria.
3
Department of Radiotherapy and Radiobiology, 1-3 Comprehensive Cancer
Center-Central Nervous System Tumors Unit (CCC-CNS), Medical University of
Vienna, Vienna, Austria.
4
Department of Neurosurgery, District Hospital,
Feldkirch, Austria.
5
Department of Internal Medicine I, Clinical Division of
Oncology, Währinger Gürtel 18-20, Vienna 1090, Austria.
Received: 17 January 2014 Accepted: 3 February 2014
Published: 25 February 2014
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Cite this article as: Hassler et al.: Response to imatinib as a funct ion of
target kinase expression in recurrent glioblastoma. SpringerPlus
2014 3:111.
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