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FMT/XCT launch: University of Zurich 1 / 20
Approaches in tumor imagingA hybrid FMT/MRI system
Markus Rudin
Katerina Dikaiou FP7/FMTXCTAline Seuwen SNFGiorgos Batsios NCCR/SNFSteffi Lehmann NCCR/SNFDivya Vats FP7/LIVIMODEFlorian Stuker SNFJan Klohs SNF
Institute for Biomedical Engineering UZH/ETHInstitute of Pharmacology and Toxicology UZH
FMT/XCT launch: University of Zurich 2 / 20
Hallmarks of cancer
Hanahan & Weinberg (2000) Cell 100, 57‐70 Luo et al. (2010) Cell 135: 823‐837
ProteasesCell marking
vessel architecture& function
glucose, energy phosphate& lipid metabolism
FMT/XCT launch: University of Zurich 3 / 20
TUMOR METABOLISM
FMT/XCT launch: University of Zurich 4 / 20
Tumor metabolism: glycolysis metabolismG Batsios, M Krajewski, M Batel, K Weiss, A Sigfridsson
Time [sec]
0
300
Lactate
Pyruvic acid
C51 colon cancer allograft s.c. in nude mice
•Glycolysis metabolism can be followed with hyperpolarized 13C spectroscopy•Injection of hyperpolarized 13C pyruvate solution•Conversion of pyruvate to lactate
FMT/XCT launch: University of Zurich 5 / 20
Metabolic changes in brain tumors
NAA
ChoIns
Cre
GL261 glioma cells in nude miceCSI, 17 days post‐injection
A Seuwen
•Differences in brain metabolite concentrations between normal and tumor tissue•MR spectroscopic imaging•Quantitative maps
Naa
CreCho
TauIns
Naa
CreCho
TauIns
Tumor tissue
Normal tissue
FMT/XCT launch: University of Zurich 6 / 20
Multimodal imaging of hypoxia signaling & angiogenesis
hallmark parameter biological information modality processHYPOXIA hypoxia tumor oxygenation PET Angiogenic
signalingHIF1a and HIF activity hypoxia signaling OPT
VEGF proangiogenic signaling OPT
SUSTAINED ANGIOGENESIS
vascular permeability sites of angiogenesis MRI Angiogenicendpointvumor blood volume total vascularization MRI
TBV and vessel size vascular architecture MRI
TISSUE INVASION AND METASTASIS
adhesion molecules activated endothelium OPT Tumor – hosttissue interactionproteases ECM degradation OPT
inflammatory cells Immune response / ECM degradation
OPT/MRI
FMT/XCT launch: University of Zurich 7 / 20
HYPOXIA
FMT/XCT launch: University of Zurich 8 / 20
Hypoxia inducible factor: HIF‐1 regulation by pO2
Hypoxia responsiveelement (HRE) promoter
PHDFIH
VHL
VHL
Proteasomaldegradation
O2
pO2
S Lehmann, S Buergi, M Desai
HO‐N
HO‐P
HO‐N
HO‐P
FMT/XCT launch: University of Zurich 9 / 20
permeabilityblood volume
angiogenesisvasodilation
VEGFi‐NOS EPO
Hypoxia
hypoxia inducible factor (HIF1)
transcription factor: HIF‐1/HIF1
binding toHRE‐elements on DNA Gene Expression
multimodal imaging of hypoxia signaling
m-Cherryviral promoter
HIF1 fluc
HIF1 stability: luminescent reporter gene
Hypoxia: 18F‐MISO PET
erythropoiesisAngiogenesis: Vascular structure & function
or CE-CT
DCE-MRI
HIF activity: reporter gene
flucVEGF
FMT/XCT launch: University of Zurich 10 / 20
hypoxia
HIF1HRE
0.0
1.0
2.0
3.0
0
5
10
15
20
0 2 4 6 8 10 12 14 16
FMIS
O T
MR
HIF
1a s
tabi
lity
or
HIF
tran
scrip
tiona
l act
ivity
Days after inoculation
HIF1a-luc (group 1)
HIF1a-luc (group 2)
pgl101-luc (group 1)
pgl101-luc (group 2)
FMISO TMR (group 1)
FMISO TMR (group 2)
multimodal hypoxia readouts
d6
d10
d8
d13
HRE‐luciferase
Multimodal hypoxia and HIF1a stability
(adapted from Lehmann et al. , PNAS 2009)
C51 colon cancer allograft s.c. in nude mice
FMT/XCT launch: University of Zurich 11 / 20
ethanolamine
oligosaccharide
phosphatidylinositol
protein, c‐terminally linked to the GPI
GPI:
glycosyl‐phosphatidyl inositol
HIF
avidin
extracellular
intracellular
cell membrane
HIF1a activity using gpi‐avidin: principle
FMT/XCT launch: University of Zurich 12 / 20
imaging label: biocytin‐Alexa594
pre contrast 60min 90min 24h
Lehmann et al., JNM (2011)
in vivo imaging of HIF1a activity using gpi‐avidin
C51 colon cancer allograft s.c. in nude mice
FMT/XCT launch: University of Zurich 13 / 20
in vivo imaging of HIF1a activity: the avidin assay
•Multimodal imaging assay using biotinylated reporter probe•Fluorescence for experimental screening•Nuclear imaging (PET, SPECT) for quantification•MRI for high spatial resolution
imaging label: 67Ga‐DOTA
C51 colon cancer & pH3SVG allograft s.c. in nude mice
imaging platform: SPECT
FMT/XCT launch: University of Zurich 14 / 20
TISSUE INVASION AND METASTASIS
FMT/XCT launch: University of Zurich 15 / 20
in vivo imaging of protease activity
Composite Unmixed GFP
ProSense680
4T1‐GFP breast cancer allograft s.c. in nude mice
imaging platform: Maestro CRi epi‐fluorescence
D Vats, C Germanier
FMT/XCT launch: University of Zurich 16 / 20
in vivo imaging of blood vessel density
4T1‐GFP breast cancer orthotopically in nude mice
imaging platform: Maestro CRi epi‐fluorescence
GFP
AngioSense680
FMT/XCT launch: University of Zurich 17 / 20
Multimodal imaging of tumors (hybrid FMT‐MRI) F Stuker, K Dikaiou, C Baltes
(adapted from Stuker et al, IEEE Trans Med Imag)
excitation module
detection module2m
•Hybrid FMT/MRI system for small animal MR scanner
imaging label: ProSense680
C51 colon cancer allograft s.c. in nude mice
FMT/XCT launch: University of Zurich 18 / 20
2nd generation hybrid FMT‐MRI Setup F Stuker, K Dikaiou
256x256 CMOS detector Filter wheel
Platform
FMT/XCT launch: University of Zurich 19 / 20
In‐vivo application in mouse model of Alzheimer‘s diseaseK Dikaiou, F Stuker, J Klohs
whitelight image MR images
imaging label: AOI987
22 month old APP23 mice and age‐matched littermates
FMT/XCT launch: University of Zurich 20 / 20
Manuscripts 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)
Lehmann S, Garcia Garayoa E, Blanc A, et al. (2011) Assessment of HIF transcriptional activity in a mouse tumor model using GPI anchored avidin ‐ a novel protein reporter for in vivo imaging. J Nucl Med 52(3):445‐52.
Stuker F, Baltes C, Dikaiou K, et al. (2011) Hybrid small animal imaging system combining magnetic resonance imaging with fluorescence tomography using single photon avalanche diode detectors. IEEE Trans Med Imaging (Epub Feb 10)
Stuker F, Ripoll J, Rudin M (2011) Fluorescence molecular tomography: principles and applications to pharmaceutical research. Pharmaceutics
Thank you!