Katerina Dikaiou FP7FMTXCT Florian Stuker SNF Steffi Lehmann NCCRSNF Divya Vats FP7LIVIMODE Sandra Buergi NCCRSNF Manoj Desai FP7LIVIMODE Markus Rudin Institute for ID: 288847
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WP7: Imaging cancer therapy
Katerina
Dikaiou
FP7/FMTXCT
Florian Stuker SNF
Steffi Lehmann NCCR/SNF
Divya
Vats
FP7/LIVIMODE
Sandra
Buergi
NCCR/SNF
Manoj
Desai
FP7/LIVIMODE
Markus
Rudin
Institute
for
Biomedical Engineering UZH/ETH
Institute
of
Pharmacology
and
Toxicology
UZHSlide2
WP7: Imaging cancer therapy - Deliverables
7.1
Preparation of HIF
transfected
colon cancer cells (9)
7.2
a) Assessment and in-vivo imaging of HIF induction in sc implanted
glioma
cells stably
transfected
with HIF reporter gene (15)
b) establishment of breast cancer model (24)
7.3 Characterization of the quantification accuracy of FMT-XCT vs. histological correlates in assessing treatment of
glioma
& mammary
cancrcinoma
at primary site metastatic sites in the lung. (32)
7.4 Characterization of the quantification accuracy of FMT-XCT vs. histological correlates in assessing treatment
of
glioma
&
mamm
. carcinoma
mouse model (
36)
7.5 Characterization of the quantification accuracy of FMT-XCT to resolve differential treatment levels in
glioma
&
mamm.carcinoma
model in the presence or absence
anti-VEGF-R
treatment as it relates to histological validation. (40)
7.6 Report on assessment of
antiangiogenic
therapy effects on HIF induction and downstream readouts of HIF (induction of
proangiogenic
factors) with FMT-XCT (46).Slide3
WP7: Imaging cancer therapy
FMT-MRI Prototype
Beta
cell
specific
imaging
:
insulinoma
Hypoxia
imaging
:
colon
carcinoma
OutlookSlide4Slide5
Multimodal
imaging
of
hypoxia
signaling & angiogenesis
parameter
biological
information
Mod
process
vascular
permeability
sites
of
angiogenesis
MRI
angiogenic
‚
endpoint
‘:
vessel
morphology
and
physiology
vumor
blood
volume
total
vascularization
MRI
TBV
and
vessel
size
vascular
architecture
MRI
hypoxia
tumor
oxygenation
PET
angiogenic
signaling
HIF1a
and
HIF
activity
hypoxia
signaling
OPT
VEGF
proangiogenic
signaling
OPT
adhesion
molecules
activated
endothelium
OPT
tumor-host
tissue
interaction
proteases
ECM
degradation
OPT
inflammatory
cells
Immune
response
/ ECM
degradation
MRISlide6
low
high
structure
vasculare
leakage
tumor
blood
volume
MRI
readouts
of
angiogenesisSlide7
1. Multimodal
imaging
of
in
tumors
(hybrid FMT-MRI)
FMT-MRI
system
FMT-MRI
detection
setup
F Stuker, K
Dikaiou
, C Baltes
(
adapted
from
Stuker et al. ,
Manuscript in prep)Slide8
FMT-MRI Performance
characterization
Spatial
accuracy
: in-plane
and
depth
resolution
In-plane
resolution
Depth
accuracy
Dose
linearity
Quantitative
analysis
:
Depth
accuracy
In-plane
resolution
(
adapted
from
Stuker et al. ,
Manuscript
in
prep
)Slide9
Multimodal
imaging
of
in
tumors
(hybrid FMT-MRI)
In vivo POC
of
simultaneous
FMT-MRI
measurement
Protease
activity
(
Prosense®) in subcutaneously
implanted C51 colon carcinoma
Limitations of
current setup: - FOV covered by
detector array too small - Dimension of
detector (32x32) too small
-
Reconstruction
does
not
yet
consider
MRI
information
(
adapted
from
Stuker et al. ,
Manuscript
in
prep
)Slide10
Ins-1E-hTMEM
HA-
mAb
Ins-1E-hTMEM
8/9mAb
Ins-1E
8/9mAb
Alexa
488
Alexa
488 +
Dapi
10
m
2. Target
specific
imaging
of
insulinoma
: TMEM27
D
Vats
, K
Dikaiou
(
adapted
from
Vats
et al. ,
Manuscript
in
prep
)Slide11
Ins-1E-hTMEM; Alexa680-8/9-mAb
Ins-1E-hTMEM
; Alexa680-anti-HA
Ins-1E ;
Alexa680-8/9-mAb
Target
specific
imaging
of
insulinoma
: TMEM27
(
adapted
from
Vats
et al. ,
Manuscript
in
prep
)Slide12
3. hypoxia inducible factor: HIF-1
a
regulation by pO
2
HO-N
HO-P
HO-N
HO-P
a
a
a
a
a
b
b
b
HRE
PHD
FIH
VHL
VHL
Proteasomal
degradation
O
2
O
2
S Lehmann, S
Buergi
, M
DesaiSlide13
regulation
of
HIF1
a
-mCherry
fusion
protein
in
cells
induced (DMOG)
normoxic
mouse embryonic fibroblasts
1)
inhibition
of
degradation
machinery
stabilizes
HIF1
a
reporter
construct
2)
stabilized
product
is
found
in
cellular
nucleus
(
transcription
factor
)
3)
s
tabilzed
product
is
transctiptionally
active
(
expression
of
downstream
genes)
hypoxia
inducible factor: HIF-1
a
regulation by pO
2Slide14
viral
promoter
HIF1
a
mCherry
permeability
blood
volume
erythropoiesis
angiogenesis
vasodilation
i-NOS
and
HO-1
VEGF
EPO
Hypoxia
hypoxia
inducible
factor
(HIF1
a
)
transcription
f
actor
: HIF-1
a
/HIF1
b
binding
to
HRE
-
elements
on DNA
Gene Expression
SV40
fluc
HRE
VEGF
Hypoxia
:
18
F-MISO PET
fluc
HIF1
a
stability
:
luminescent
reporter
gene
HIF
activity
:
bioluminescent
reporter
gene
Angiogenesis
: MRI
vascular
permeability
Multimodal
imaging
hypoxia
signalingSlide15
hypoxia
HIF1
a
HRE
multimodal hypoxia readouts
d6
d10
d8
d13
C51: HRE-
luciferase
Multimodal
imaging
hypoxia
signaling
(
adapted
from
Lehmann et al. , PNAS 2009)Slide16
max
min
max
min
max
min
max
min
H & E
pimonidazole
HIF1
a
GLUT1
CD31
day 7 8 9 11 14
(
adapted
from
Lehmann et al. , PNAS 2009)
Multimodal
imaging
hypoxia
signalingSlide17
permeability
blood
volume
erythropoiesis
angiogenesis
vasodilation
i-NOS
and
HO-1
VEGF
EPO
Hypoxia
hypoxia
inducible
factor
(HIF1
a
)
transcription
f
actor
: HIF-1
a
/HIF1
b
binding
to
HRE
-
elements
on DNA
Gene Expression
Multimodal
imaging
hypoxia
signaling
Feedback
Non-
hypoxic
HIF1a
regulationSlide18
Multimodal
imaging
hypoxia
signaling
S Lehmann
(
adapted
from
Lehmann et al. ,
Manuscript
in
prep
)Slide19
Multimodal
imaging
hypoxia
signaling
(
adapted
from
Lehmann et al. ,
Manuscript
in
prep
)Slide20
Second generation FMT-MRI
-
increased
dimension
of
SPAD (FSt, KDi) - improved reconstruction, irregular shaped object (KDi) and accounting for tissue heterogeneity - application:
hypoxia
signaling
(FMT)
and
angiogenesis
(MRI)
Establishment of breast tumor model
: - sc and orthotopic (DVa
) - evaluation of
novel protease probes (DVa, LIVIMODE)
Novel hypoxia assays using IFPs:
- fluorescence assays for
HRE (
SBu
,
MDe
)
4.
Orthotopic
brain
tumor
model
: -
hypoxia
signaling
in
glioma
models
(
SBu
)
OutlookSlide21Slide22
Manuscript published
S.Lehmann
, D Stiehl, M
Honer
et al.
Longitudinal and multimodal
in vivo
imaging of tumor hypoxia and its downstream molecular events PNAS (2009)Manuscript in preparationS Lehmann, R Keist, M Rudin. GPI anchored avidin- a novel protein reporter for in vivo imaging S Lehmann, D Stiehl, M Dominietto et al. Longitudinal imaging of the pharmacological inhibition of PHDs in mouse tumor allograftsD Vats, H Wang, K
Dikaiou
et al.
Multimodal imaging of pancreatic β-cells in vivo via TMEM27 antibody
F Stuker, C Baltes, K
Dikaiou
et al
Hybrid small animal imaging system combining magnetic resonance imaging with fluorescence tomography using single photon avalanche diode detectors
Manuscripts