Preclinical Efficacy of the c-Met Inhibitor
CE-355621 in a U87 MG Mouse Xenograft Model
Evaluated by18F-FDG Small-Animal PET
Jeffrey R. Tseng*1, Keon Wook Kang*2, Mangal Dandekar1, Shahriar Yaghoubi1, Joseph H. Lee3, James G. Christensen3,
Stephen Muir4, Patrick W. Vincent5, Neil R. Michaud5, and Sanjiv S. Gambhir1,6
1Molecular Imaging Program at Stanford, Bio-X Program, and Department of Radiology, Stanford University, Stanford, California;
2Department of Nuclear Medicine, National Cancer Center, Goyang, South Korea;3Cancer Biology, PGRD-La Jolla Laboratories, Pfizer
Inc., La Jolla, California;4Oncology, PGRD-New London, Pfizer, Inc., New London, Connecticut;5Cancer Biology, PGRD-Groton
Laboratories, Pfizer Inc., Groton, Connecticut; and6Department of Bioengineering, Stanford University, Stanford, California
The purpose of this study was to evaluate the efficacy of CE-
355621, a novel antibody against c-Met, in a subcutaneous
U87 MG xenograft mouse model using18F-FDG small-animal
PET. Methods: CE-355621 or control vehicle was administered
Drug efficacy was evaluated over 2 wk using18F-FDG small-
sults: The maximum %ID/g (percentage injected dose per gram
of tissue) of18F-FDG accumulation in mice treated with CE-
355621 remained essentially unchanged over 2 wk, whereas
the %ID/g of the control tumors increased 66% compared with
the baseline. Significant inhibition of
was seen 3 d after drug treatment, which was earlier than the in-
hibition of tumor volume growth seen at 7 d after drug treatment.
Conclusion: CE-355621 is an efficacious novel antineoplastic
lier than tumor volume changes in a mouse xenograft model.
Theseresults support the use of18F-FDG PET to assess early tu-
mor response for CE-355621.
Key Words: CE-355621; c-Met inhibitor;18F-FDG; microPET;
drug evaluation; therapy response
J Nucl Med 2008; 49:129–134
CE-355621 is a novel monoclonal antibody that binds
to the extracellular domain of c-Met (1). c-Met is a receptor
tyrosine kinase involved in multiple pathways linked to
cancer—such as cell migration, invasion, proliferation, and
angiogenesis—and is upregulated in a large number of
human cancers (2,3). This novel antibody may serve as an
antineoplastic chemotherapeutic by disrupting several of
these pathways. Tumor growth has been inhibited in several
tumor xenograft models in which the antibody blocks au-
tocrine activation of c-Met from hepatocyte growth factor
(HGF) released from the tumors (1).
18F-FDG PET has been validated as an imaging modality
to assess a wide range of cancers for a wide range of
indications—including diagnosis, staging, and restaging—
and to assess response to therapy (4). With the development
of microPET scanners for small animals (5), assessment of
tumor xenograft mouse models with
possible for preclinical oncology research. Several authors
have used18F-FDG microPET to assess various therapies in
mouse tumor xenograft models (6–9). In addition, several
studies have compared18F-FDG microPET with an alter-
native proliferation tracer, 39-deoxy-39-18F-fluorothymidine
(18F-FLT), to assess tumor xenograft response to a variety
of therapies (10–13). We have recently shown that micro-
PET studies are reproducible with moderately low vari-
ability, such that serial studies on mouse tumor xenografts
can be reliable in assessing therapy response (14,15).
This study was performed to assess the preclinical ef-
ficacy of CE-355621 to inhibit18F-FDG accumulation in
vivo using a U87 MG human glioblastoma mouse xenograft
tumor model. We show that CE-355621 inhibits18F-FDG
accumulation earlier than changes in tumor volume, which
supports the use of18F-FDG PET in human clinical trials
for early therapy monitoring. These preclinical18F-FDG
PET results may be useful to predict the success of future
human clinical trials and may prove useful in accelerating
MATERIALS AND METHODS
CE-355621 (Pfizer Inc.) is a monoclonal antibody antagonist
that binds to the extracellular domain of the c-Met tyrosine kinase.
A stock solution of 10 mg/mL CE-355621 was stored in a solution
Received Dec. 15, 2006; revision accepted Sep. 18, 2007.
For correspondence or reprints contact: Sanjiv S. Gambhir, MD, PhD,
Molecular Imaging Program at Stanford (MIPS), Division of Nuclear Medicine,
Departments of Radiology and Bioengineering, Bio-X Program; The James H.
Clark Center, 318 Campus Dr., East Wing, 1st Floor, Stanford, California
*Contributed equally to this work.
COPYRIGHT ª 2008 by the Society of Nuclear Medicine, Inc.
CE-355621 EFFICACY WITH18F-FDG MICROPET • Tseng et al.129
of 20 mM sodium acetate, pH 5.5, and 140 mM sodium chloride at
4?C. Before use, the drug was dissolved in phosphate-buffered
saline to a final concentration of 1 mg/mL.
modified Eagle media, supplemented with 10% fetal bovine serum
(Invitrogen). Cells were grown in T-225 flasks at 37?C with 5%
carbon dioxide in a humidified incubator. Cells were harvested or
split at approximately 90% confluence by trypsinization. For im-
plantation into nude mice, cells were resuspended in phosphate-
buffered saline and incubated on ice until injection.
Mouse Xenograft Model
Animal protocols were approved by the Stanford Administra-
tive Panel on Laboratory Animal Care. Forty-five 8-wk-old female
nude (nu/nu) mice (Charles River Laboratories) were injected
subcutaneously with 1 · 106U87 MG cells in the right flank while
anesthetized with 2% isoflurane in 1 L of oxygen. Mice were
weighed and tumors were measured with external calipers every
2–3 d. Tumor volumes were estimated as length · width · width
O 2. After 6 d, when tumors reached an approximate volume of
200 mm3, 32 mice were selected for further study. During the
study, 5 animals died while they were in the anesthesia chamber;
the deaths were likely due to hypothermia from a malfunctioning
heating pad. One mouse in the drug-treated group was excluded,
as no drug was detected in the blood at the end of the study. The
final count consisted of 12 mice in the drug-treated group and 14
mice in the control group.
The drug dosing and imaging schedules were as follows. Mice
were administered one dose of 200 mg CE-355621 (in a total
volume of 200 mL) or the control vehicle saline solution by in-
traperitoneal injectiononday 7after tumorcell inoculation. Onday
6, a baseline microPET scan was performed before the drug dose,
followed by imaging on days 8, 10, 14, and 16. The control arm of
the study was stopped after day 16 because the tumor burden was
and a final scan was obtained on day 21.
Before imaging, mice were fasted for 4 h and had free access to
water. Approximately 7.4 MBq (200 mCi) of18F-FDG (Siemens/
PETNET) were injected via the tail vein. Tail vein blood glucose
levels were recorded after injection. One hour after injection, mice
Inc.). The scanner has an approximate spatial resolution of 2 mm in
each orthogonal direction (17), which was confirmed by phantom
studies in our laboratory. Mice were maintained under isoflurane
anesthesia and on a heating pad during the injection, uptake period,
physiologic body temperatures while under anesthesia. A 5-min
static acquisition was performed with no attenuation correction,
as described previously (14). Images were reconstructed using a
2-dimensional ordered-subsets expectation maximization algo-
rendering of an18F-FDG microPET scan is included in Supple-
mental Video 1 (supplemental material is available online only at
microPET Image Analysis
Ellipsoidal regions of interest (ROIs) were drawn around the
edge of the tumor activity using AMIDE software (19). The maxi-
mum, upper 20% of voxels, and mean activities were recorded.
The percentage injected dose per gram (%ID/g) and standardized
uptake value (SUV) were calculated as follows: %ID/g 5 ROI
activity O injected dose · 100%. SUV 5 ROI activity O injected
dose · body weight. Spheric background ROIs with a diameter of
4 mm were drawn in homogeneous areas adjacent to the tumors to
calculate tumor-to-background ratios. No partial-volume correc-
tion was applied as all tumors had size measurements . 6 mm,
which was greater than 3 times the full width at half maximum
resolution of the microPET scanner (20).
Two-tailed Student t tests were performed to determine signif-
icant differences between 2 groups of data. Paired t tests were
used when comparing changes within the same animals over time.
A P value , 0.05 was chosen to indicate significance. Data were
reported with standard errors of the mean.
CE-355621 Inhibits Tumor Xenograft Growth
Nude mice were inoculated with U87 MG human glio-
blastoma cells, and tumor volumes were followed for ap-
proximately 2 wk. The tumor volume growth curves for
U87 MG tumor xenografts are shown in Figure 1. Compared
with the baseline day 6 values, tumor growth in both the
drug-treated group and the control group was significantly
increased on all subsequent days after baseline. When com-
paring the drug-treated group with the control group, CE-
355621 significantly inhibited tumor growth on day 14 (7 d
(P , 0.001). A significant difference was also found on day
grafts in nude mice measured by external calipers. CE-355621
or control vehicle was administered on day 7 after tumor cell
inoculation. Error bars represent SEM.
Tumor volume growth curves for U87 MG xeno-
130THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 1 • January 2008
16 (P , 0.001); however, no significant difference was seen
at the earlier times points on days 8 and 10.
Mouse body weights of both groups had small increases
over time. On day 16, the control group increased 8.7%
compared with the day 6 baseline, whereas the drug-treated
group increased 3.5%. This larger increase in the control
group was significantly different (P 5 0.02) from that of
the drug-treated group on day 16 and was likely related to
the differences in tumor weight between groups.
Blood glucose measurements at the time of injection
ranged widely from 20 to 212 mg/dL (mean 6 SD, 116 6
47 mg/dL). There was no significant difference between the
drug-treated group and the control group at each time point
in the study. In addition, there was no significant difference
between the pretreatment baseline values and each succes-
sive posttreatment value for the drug-treated group and the
control group (Supplemental Table 1).
CE-355621 Inhibits18F-FDG Accumulation in U87 MG
18F-FDG accumulation was measured in the tumor xeno-
grafts using microPET to assess changes in the control mice
(Figure 2A) compared with mice treated with CE-355621
(Fig. 2B). The maximum %ID/g of18F-FDG accumulation
increased steadily over time for the control group (Fig. 3A).
6, and the final maximum %ID/g on day 16 increased 66%
compared with baseline. In comparison, the drug-treated
group had a small increase on day 8 compared with baseline
(P 5 0.008), but days 10–22 had no significant differences
compared with baseline (Fig. 3A).
When comparing the drug-treated group with the control
group, the maximum %ID/g of the drug-treated group was
significantly less than that of the control group (P 5 0.03)
on day 10 (3 d after drug treatment). The groups remained
significantly separated on days 14 and 16 (P 5 0.003 and
P , 0.001).
On day 8 (1 d after drug treatment), the maximum %ID/g
for the drug-treated and control groups overlapped and were
not significantly different (P 5 0.68). Because the day 6
baseline values for the drug-treated group were higher than
those for the control group, the data for the groups were
normalized to their respective day 6 baseline values (Fig.
3B). Using the normalized data, the drug-treated group
showed a nearly significant difference on day 8 (1 d after
treatment) compared with that of the control group (P 5
0.06). Thereafter, each successive time point showed a
significant separation between groups (P 5 0.005, P 5
0.002, and P , 0.001).
Tumors were also analyzed using the mean %ID/g, which
had some differences compared with the maximum %ID/g
peaked on day 10 and then decreased for the remaining time
points. A significant difference between the drug-treated
group and the control group was seen only on day 10 (P 5
0.02). Inspection of the images revealed that control group
areas consistent with tumor necrosis (Fig. 5). To compensate
for the tumor necrosis, the images were reanalyzed by
selecting the average activity of the hottest 20% of voxels.
This reflected the most metabolically active areas of the
tumor and tended to exclude the regions with tumor necrosis
(Fig. 4B). The drug-treated group showed a significant
difference on day 10 (P 5 0.01), which persisted on days
14 (P 5 0.01) and 16 (P , 0.001), similar to the maximum
%ID/g analysis. Analysis of tumor-to-background ratios and
of the %ID/g analysis. Analysis of normalized mean %ID/g,
upper 20%, tumor-to-background ratios, and SUVs also
revealed similar trends and significance values.
CE-355621 is a novel antineoplastic antibody directed
against the c-Met tyrosine kinase receptor. The antibody
antagonizes c-Met function by blocking the binding of the
ligand HGF to c-Met and by blocking ligand-dependent
c-Met activation, which subsequently induces internaliza-
tion and downregulation of the receptor. Several tumor cell
lines express both HGF and c-Met, including the U87 MG
human glioblastoma cell line (21). These tumor lines serve
as a model to study the resulting autocrine activation of
c-Met. Preliminary studies have shown that tumor growth
has been inhibited in several tumor xenograft models, in-
cluding U87 MG, by blocking the autocrine activation of
c-Met from HGF released from the tumors (1). Because
c-Met is upregulated in many human cancers, it is an
from nude mice with U87 MG xenografts. Mice were scanned
prone with the tumor xenograft in the right flank (arrows). Tumor
volumes and maximum %ID/g are listed below the images. CE-
355621 or control vehicle was administered on day 7. (A)18F-
FDG accumulation increased over time in a representative
control mouse xenograft. (B)18F-FDG accumulation on days
8–21 in a representative drug-treated mouse xenograft was
similar to that of baseline day 6.
Representative axial18F-FDG microPET images
CE-355621 EFFICACY WITH18F-FDG MICROPET • Tseng et al.131
attractive novel target for cancer therapy, and its potential
application has been recently reviewed by Christensen et al.
In this study, CE-355621 significantly inhibited18F-FDG
accumulation in U87 MG tumor xenografts compared with
that of controls. U87 MG cells were specifically chosen to
model of the c-Met/HGF autocrine loop. These findings
suggest that the drug can inhibit the neoplastic process, as
reflected by the downstream effect of glucose metabolism
seen on18F-FDG microPET studies. No overall decrease in
18F-FDG accumulation was seen in the drug-treated group
compared with the baseline values; however, a targeted
agent such as CE-355621 may exhibit cytostatic effects
rather than cytotoxic effects, which is supported by our
data. These preclinical results support the use of this novel
drug in clinical trials and suggest that clinical18F-FDG
PET studies may be useful to follow the early response to
Assessment of early response to therapy is desirable
because it may allow early halting of ineffective treatments
to avoid toxicities and allow switching to potentially
effective treatments. In our study the18F-FDG accumula-
tion curves showed a significant separation between the
drug-treated group and control group 3 d after drug treat-
ment (day 10) and a nearly significant separation 1 d after
drug treatment. In comparison, separation of the tumor
volume curves was seen later at 7 d after drug treatment
(day 14). Early changes in18F-FDG accumulation com-
pared with volume changes were also seen by Leyton et al.,
who studied the efficacy of the cytotoxic agent cisplatin in
an18F-FDG microPET study (13). Their study showed a
18F-FDG accumulation between the drug-
treated and control groups at 24 h, whereas a difference in
tumor volume was seen later at 48 h. Several other groups
(8,10–12) have tracked changes in tumor volume and18F-
FDG accumulation; however, unlike the current study, no
FDG accumulation for U87 MG xeno-
grafts plotted over time. CE-355621 or
control vehicle was administered on day
7. Error bars represent SEM. (A) Maxi-
mum %ID/g values are plotted. (B) Max-
imum %ID/g values normalized to the
baseline day 6 value are plotted.
Maximum %ID/g of
U87 MG xenografts plotted over time.
CE-355621 or control vehicle was ad-
ministered on day 7. Error bars represent
SEM. (A) Mean %ID/g values are plotted,
revealing a significant separation be-
tween drug-treated group and control
group only on day 10. (B) Upper 20% (of
voxels) %ID/g values are plotted, reveal-
ing a significant separation on days 10,
14, and 16, similar to the maximum %ID/g
values in Figure 3A.
18F-FDG accumulation in
132THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 1 • January 2008
direct statistical comparisons were made in any of these
prior studies to assess which changes occurred earlier.
Further support for early response evaluation was shown
by Cullinane et al. in a mouse xenograft18F-FDG microPET
study (6).18F-FDG accumulation was rapidly inhibited at
4 h after treatment with the targeted receptor tyrosine kinase
imatinib (Gleevac). These18F-FDG microPET findings are
similar to clinical PET studies showing that decreases in
18F-FDG activity preceded change in tumor size and could
predict prognosis in gastrointestinal stromal tumors (22–24)
and lymphoma (25). The effects seen with18F-FDG micro-
PET in our study occurred on the time scale of days in a
rapidly growing tumorxenograftmodel.When translating to
clinical human studies, tumors are likely to exhibit slower
growth, such that serial assessment will more likely be made
in a time scale of weeks rather than days. Regardless of the
overall time scale, we anticipate that earlier changes seen
with18F-FDG PETas compared with conventional anatomic
imaging (e.g., CT, MRI, and ultrasound) will significantly
slowly, then the effects of a cytostatic drug in an18F-FDG
PET scan may not be seen for long periods of time; however,
this limitation is also true for currently used anatomic im-
PETresults can predict the success of drugs in clinical trials.
To our knowledge, the ability to prospectively predict the
clinical efficacy of a novel drug using preclinical18F-FDG
microPET studies has not been reported previously. If CE-
355621 proceeds to clinical trials, it would be important to
correlate the microPETresults with18F-FDG PET studies in
human trials. Preclinical animal models have had variable
success in predicting clinical success (26,27). However,
given the proven utility of18F-FDG microPETand PET for
therapy monitoring, we believe that preclinical18F-FDG
microPET may be a more useful predictor of the success of
human clinical trials and may prove useful in accelerating
drug development. These types of studies are required to
assist the decision-making process of whether to proceed
with a drug after preclinical animal testing. Furthermore,
assessment of cytostatic targeted agents has become an
important issue in clinical trials (28). Traditional toxicity-
based endpoints may not be appropriate to evaluate the
efficacy of cytostatic targeted therapies (28,29). Newer
markers may be necessary to adequately assess phase 1 dose
selection trials as well as phase 2 efficacy trials.18F-FDG
PET has the potential to fulfill these roles.
An additional advantage of microPET is the ability to
cannot be assessed by external caliper measurements. We
found that control tumors of greater than approximately
1,000 mm3developed central photopenia consistent with
tumor necrosis. This effect was seen by visual inspection of
the images and may help explain why the maximum %ID/g
continued to increase over time for the control tumors,
whereas the mean %ID/g decreased. Interpretation of data
from tumors with volumes . 1,000 mm3in this xenograft
model should be given with caution as tumor necrosis can
have a large contribution to changes in tumor volume and
mean tracer accumulation.
One limitation of our study was that we used only a single
cell line in a subcutaneous mouse xenograft model that was
responsive to the drug treatment. As a tumor model, subcu-
taneous xenografts may not be entirely representative of
model or genetically engineered mouse models may provide
additional insight into the drug’s efficacy and the utility of
18F-FDG microPET. In addition, studies with both chemo-
sensitive lines as well as chemoresistant lines are needed to
determinewhether18F-FDG microPET can predict response
to drug treatment in both types of cell lines. In clinical trials,
both positive and negative results can impact the decision to
proceed or terminate a drug in development. Assessing cell
lines of different cancer types could also determine whether
the drug is applicable across a broad range of cancers.
Insights may be also obtained by assessing rapidly growing
cell lines versus slowly growing cell lines. Further in vitro
studies may also provide insight into the mechanism of
CE-355621 on glucose metabolism as reflected by18F-FDG
accumulation. Assessment with other PET tracers—such as
18F-FLT for proliferation,18F-annexin-V for apoptosis, and
may accumulate in areas of inflammation, early assessment
of tumor activity may be masked by an inflammatory
response to therapeutics. The use of18F-FLT may provide
additional ways to assess early tumor response (10–13,32).
Another limitation of our study is that the
accumulation values were not corrected for blood glucose
values. Wahl et al. reported that hyperglycemia can reduce
18F-FDG accumulation in rat tumors; however, other organs
such as liver, spleen, heart, and muscle showed no signif-
icant difference (33). Recently, 2 groups have reported the
effects of various anesthetic agents and fasting times in
tumor-bearing mice (34,35). These studies highlight the
complex relationship of
18F-FDG accumulation, blood
glucose levels, fasting state, and anesthesia. We attempted
to control for these effects by using the same fasting, an-
esthesia, and scanning protocols for all mice. Our initial
efforts to adjust18F-FDG accumulation in tumors with a
glucose correction factor have not improved the accuracy of
from a representative control
group mouse with large ne-
crotic U87 MG tumor xeno-
graft (arrow). Central
necrosis is evident as a cen-
tral photopenic area. Maxi-
mum %ID/g, upper 20% (of
voxels) %ID/g, and mean
%ID/g are listed below the
CE-355621 EFFICACY WITH18F-FDG MICROPET • Tseng et al.133
the measurements (15). Further investigations into this im- Download full-text
portant issue are ongoing and necessary.
CE-355621 is an efficacious novel antineoplastic agent,
which inhibits18F-FDG accumulation in a mouse xenograft
model compared with that of control animals. Significant
inhibition of18F-FDG accumulation was seen 3 d after drug
treatment, which was earlier than the inhibition of tumor
encourage further testing of this novel targeted agent in
clinical trials using18F-FDG PET to assess early therapy
technical assistance and helpful discussions. Funding was
provided by Pfizer, Inc., and the NCI’s Small Animal Imag-
ing Resource Program (SAIRP grant R24CA92862).
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134THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 1 • January 2008