WP6_Garofalakis_Lime - Lungeninformationsdienst

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FMT – XCT meeting, Heraklion, March 26th
Wp6: Cancer imaging with
focus on breast cancer
Frederic DUCONGE, Anikitos GAROFALAKIS
Nicola MACKIEWIZC, Agnel CIBIEL
CEA, DSV, I2BM, SHFJ, LIME, INSERM U 803
Laboratoire d’imagerie de l’expression des gènes
Anikitos GAROFALAKIS
CEA, I2BM, SHFJ, LIME, INSERM U803
1
Background
Phantoms is the standard way of evaluating an optical tomogrpher
Realistic conditions are achieved by the use of animal models
Objectives of Wp6:
To provide key fluorescence probes and cancer animal models
Quantitatively examine FMT performance to visualize disease
processes in-vivo
To predict clinical utility
Anikitos GAROFALAKIS
CEA, I2BM, SHFJ, LIME, INSERM U803
2
Overview
• Animals models of breast cancer
cell lines, transgenic mouse models
• Fluorescent probes
• Instrumentation and measuremements
• Conclusions
Anikitos GAROFALAKIS
CEA, I2BM, SHFJ, LIME, INSERM U803
3
Mammary Tumor Xenografts
MDAMB-231 human breast adenocarcinoma cells (in
RAG-1immunodeficient mice)
Well validated model for tumor growth and metastasis via overexpression of MT4-MMP (human Membrane Type-4 Matrix
MetalloProteinases)
NIH-MEN2A
MCF-7 for probe development(aptamers)
U87MG brain tumor cell line
Anikitos GAROFALAKIS
CEA, I2BM, SHFJ, LIME, INSERM U803
4
Mammary tumor transgenic models
Polyoma Middle T (PyMT) oncoprotein under the
control of the Mouse Mammary Tumor Virus ‘Long
Terminal Repeat’ (MMTV LTR).
Optical Imaging
Histological
staging
Hyperplasia
Adenoma
Early Carcinoma
Late Carcinoma
FDG PET
SPECT TcO4
CT
5
Anikitos GAROFALAKIS
15
CEA, I2BM, SHFJ, LIME, INSERM U803
weeks
5
Tumoral angiogenesis
- At the end of an avascular phase, the tumor has consumed most of nutrients available in its
close environment. Then, most of the cancer cells are in a quiescent or necrotic state.
- To keep on growing, the tumor has to obtain new sources of nutrients: that is the angiogenic
process.
Anikitos GAROFALAKIS
CEA, I2BM, SHFJ, LIME, INSERM U803
6
Tumoral angiogenesis at a molecular level
Anikitos GAROFALAKIS
CEA, I2BM, SHFJ, LIME, INSERM U803
7
Fluorescent Probes
Commercial probes
Prosense 680
Cathepsin
activity
Integrinsense680 (VisenMedical, USA)
AngioStamp (Fluoptics, France)
Integrin
localization
Custom-made probes
PEG nano-micelles
Anikitos GAROFALAKIS
CEA, I2BM, SHFJ, LIME, INSERM U803
Unspecific
binding of
tumors
8
Tomographic(3D) Imaging
Anikitos GAROFALAKIS
CEA, I2BM, SHFJ, LIME, INSERM U803
9
Preclinical imaging facilities at SHFJ center
Nuclear
imaging
Optical
imaging
Anikitos GAROFALAKIS
CEA, I2BM, SHFJ, LIME, INSERM U803
10
Multimodality Imaging for intregrating the derived information
Glucose consumption related
to Tumor volume(FDG)
Molecular information of tumor
related processes(Optical Probes)
Anatomical information
Anikitos GAROFALAKIS
CEA, I2BM, SHFJ, LIME, INSERM U803
11
MDAMB-231/Prosense – Cathepsin activity
1 mm
Anikitos GAROFALAKIS
Signal of optical in the
surrounding tissue
90.84 %
Volume of tumor in the
common area
27.86%
CEA, I2BM, SHFJ, LIME, INSERM U803
12
MDAMB-231/Prosense – Cathepsin activity
Longitudinal studies
3 h after injection
Anikitos GAROFALAKIS
24 h
48 h
VOLUME
(mm3)
MEAN VALUE
(a.u.)
Prosense_1st Day
188
3.97
Prosense_2nd Day
302
3.45
Prosense_3rd Day
581
3.65
CEA, I2BM, SHFJ, LIME, INSERM U803
13
MDAMB-231/Integrisense – Integrin localization
1 mm
Integrin is found predominently in the base of the tumor
Anikitos GAROFALAKIS
89.76 %
signal of optical in the surrounding
tissue
11.48 %
volume of tumor in the common
area
CEA, I2BM, SHFJ, LIME, INSERM U803
14
MDAMB-231/Nano micelle imaging
1 mm
Anikitos GAROFALAKIS
68 ± 15 %
signal of optical in the surrounding area
17 ± 4 %
Optical volume in the common region
CEA, I2BM, SHFJ, LIME, INSERM U803
15
PC12/MEN2A/Prosense – Cathepsin activity
fusion
PET
Opt
66.5 ± 1.8 %
signal of optical in the surrounding area
31.8 ± 2.0 %
Optical volume in the common region
Volume
Mean
StdDev
Min
Max
Prosense_DAY_1
317.781
3.5
2.1
1.2
16.6
Prosense_DAY_2
412.45
3.5
2.1
0.9
15.0
Prosense_DAY_3
373.337
4.0
2.4
1. 1
13.0
Anikitos GAROFALAKIS
CEA, I2BM, SHFJ, LIME, INSERM U803
16
fDOT/CT imaging of tumour angiogenesis using AngioStamp®
X-Ray CT
Anikitos GAROFALAKIS
fDOT
CEA, I2BM, SHFJ, LIME, INSERM U803
17
fDOT/CT imaging of tumour angiogenesis using AngioStamp®
Anikitos GAROFALAKIS
CEA, I2BM, SHFJ, LIME, INSERM U803
18
Integrisense and AngioStamp comparison
Integrisense 0h
Integrisense 3h
Tumor volume ~ 730 mm3
60,2
%
signal of optical in the surrounding
31,42
%
signal of optical in the surrounding
30,01
%
volume of tumor in the common area
32,55
%
volume of tumor in the common area
RAFT - RGD 2h
RAFT-RGD 0h
Tumor volume ~ 670 mm3
47,29
%
signal of optical in the surrounding
29,98
%
volume of tumor in the common area
Anikitos GAROFALAKIS
36,2
%
signal of optical in the surrounding
36,48
%
volume of tumor in the common area
CEA, I2BM, SHFJ, LIME, INSERM U803
19
Mammary tumor transgenic mice models
Evaluation of the vascular permeability
8 weeks
10 weeks
12 weeks
intra venous injection of Superhance™680 (Visen Medical)
Superhance binds to albumin and has a half-life in plasma of
approximately 2 h
Surf.Activity (cpm/mm2)
25 min post i.v.
60 min post i.v.
1000000
800000
600000
PyMT 2001 8 weeks
PyMT 2001 10 weeks
PyMT 2001 12 weeks
400000
200000
0
0
120 min post i.v.
100
200
300
400
500
Time post i.v. injection (min)
increased vascular permeability of the tumours during
tumoral development.
Anikitos GAROFALAKIS
CEA, I2BM, SHFJ, LIME, INSERM U803
20
Conclusions and perspectives
Development of a method for multimodal measurements on tumors
Characterization of important tumoral processes from complementary
PET/FMT/CT measurements
Different tumor cell lines and mouse models available for further testing
and comparison
Integration of microscopic information (Endoscopic imaging)
Development of Aptamer for specific Tumor labelling
Further experiments to complete the study
Anikitos GAROFALAKIS
CEA, I2BM, SHFJ, LIME, INSERM U803
21
Advancement of programme
Planned Deliverables (month of delivery planned at start of first year)
6.1 To develop and characterize molecular probes (mo.9, 18)
6.2 Prepare and characterize mammary cancer animal models (mo.18)
6.3 Breed and making available PyMT animal models (mo.24)
6.4 Develop U87 animal models (mo.27)
6.5 Study and report the quantitative accuracy of FMT-alone and FMT-XCT in
resolving tumors (mo. 36)
6.6 Study and report cancer detection performance in various organs (mo. 40)
6.7 Report the overall imaging performance. (mo.42)
Status of achievement
6.1-6.3 : achieved and continued.
6.4: to achieved
6.5: already started awaits comparison
6.6-6.7: to begin after 6.5
Anikitos GAROFALAKIS
CEA, I2BM, SHFJ, LIME, INSERM U803
22
Aknowledgements
Experimental molecular imaging laboratory (LIME)
Bertrand Tavitian
Frédéric Ducongé
Raphael Boisgard
Abertine Dubois
Carine Pestourie
Anikitos GAROFALAKIS
CEA, I2BM, SHFJ, LIME, INSERM U803
23
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