approaches in tumor imaging a hybrid fmt/mri system · 2011-12-29 · fmt/xct launch: university of...

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


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


TUMOR METABOLISM


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


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


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


HYPOXIA


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


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


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)



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


imaging label: biocytin‐Alexa594

pre contrast 60min 90min 24h

Lehmann et al., JNM (2011)

in vivo imaging of HIF1a activity using gpi‐avidin



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


TISSUE INVASION AND METASTASIS


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


in vivo imaging of blood vessel density

4T1‐GFP breast cancer orthotopically in nude mice

imaging platform: Maestro CRi epi‐fluorescence

GFP

AngioSense680


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



2nd generation hybrid FMT‐MRI Setup F Stuker, K Dikaiou

256x256 CMOS detector Filter wheel

Platform


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


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!

approaches in tumor imaging a hybrid fmt/mri system · 2011-12-29 · fmt/xct launch: university of...

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