As Tool for Personalized Medicine - European Commission · Nuklearmedizinische Klinik im Klinikum rechts der Isar. der Technischen Universität München. Molecular Imaging. As Tool

Nuklearmedizinische Klinik im Klinikum rechts der Isarder Technischen Universität München

Molecular Imaging

As Tool for Personalized Medicine Markus SchwaigerTechnische Universität MünchenGermany

EC Conference European Perspective in Personalised Medicine Brussels 12-13 May 2011

Early Diagnosis and Risk Profiling Therapy Selection and Monitoring (Interv. and Pharm.)

Environment / Prevention (Life Style Modifications)

Gen Expr ProfileTissue arraysCell Genetic

Clinical DataFamiliy hx / Demographics

Environmental Risk Factors / Traetments

GenomicsSNPs

Genome-scale sequence

Proteomics Metabolomics

Serum and TissueBiomarkers

Molecular ImagingStructureFunction

Molecular Biology

Prediction

Molecular Medicine

What is Molecular Imaging?Non-invasive visualization of biologic and

cellular processes using molecular structures as imaging targets

InstrumentationImaging probes

What is Molecular Imaging?Non-invasive visualization of biologic and

cellular processes using molecular structures as imaging targets

InstrumentationImaging probes

Development of Imaging Technologies

Weissleder R, Pittet MJ; et al, Nature 2008, 580-589.

PET PET-CT

MRI

UltrasoundInterventional

Ultrasound

X-rays X-rays CT MSCT MSCT

LN-MRI Diffusion MRI

Diaphanoscopy Fibre optic FRI BLI HR-FRI Lifetime FRI

DOT FMT FPT FMT-CT FMT-MRI

MicroendoscopyMPMConfocalOCT,OFDIEpifluorescenceBright fieldBright field

Mic

ros

copy

Tom

ogra

phy

Mac

rosc

opi

cre

flect

anc

eX-

rays

an

d C

TU

ltras

oun

dM

R IP

E T

Clin

ical

pr

acti

ce

Opt

ical

de

velo

pme

nt

1900 1920 1940 1960 1970 1980 1985 1990 1995 2000 2001 2002 2003 2004 2005 2006 2007 2008 2010

MR PET Insert

Integrated MR/PET

0.03 kg0.30 kg

5.00 kg20.00 –

60.00 kg

Pre-clinical Clinical

3.00 kg

70.00 –150 kg

Courtesy National Research Institute-

OSKI- Hungary Brain Matters at Harbor-UCLA

National Cancer

Center-Japan

ErasmusMC, InsightMR I&

UNM, US

Courtesy UNM -US

From Animal to Humans

Translational Research

MR/PET München (TUM/LMU), Teil der DFG-Großgeräteinitiative

mMR- First MR/PET for Simultaneous WB -Imaging

MR/PET München (TUM/LMU), Teil der DFG-Großgeräteinitiative

Biograph mMR: Initial Results

Fürst et al8

MR/PET Workflow – Simultaneous Acquisition

Bed Position 1

Bed Position 2

Bed Position 3

Less than 30 mins for combined MR/PET Whole Body

Multi-Spectral Optoacoustic Tomography (MSOT)10-100micron resolution ● 5 – 30mm penetration

Institute for Biological & Medical Imaging (IBMI)

Multi-spectral illumination

Photon correction

Ultra wide-band acoustic detection

Spectral projection inversion (SPI)

IN: LIGHT OUT: SOUND

5 mm

6 mm

Ex-vivo histology / microscopy

mCherry expression

In-vivo MSOT

0.4mm 0.4mm

Nature Photonics 3, 412-417 (2009)

Intraoperative Imaging

Specific staining of CT26 tumors (d14)8h after i.v. injection of cmHsp70.1 mAb

Visible colors Fluorescence image (Cy5.5)

tumor

liverliver

tumor

32

Imaging Signals for Guidance of Interventions (Sugery/Endoscopy)

What is Molecular Imaging?Non-invasive visualization of biologic and

cellular processes using molecular structures as imaging targets

InstrumentationImaging probes

Cellular Stress

EnergyMetabolism

Proliferation

Perfusion

Metastasis

Angiogenesis

Hypoxia

Characterisation of Individual Tumor Biology Biologic Knowledge Imaging Tools

Molecular Imaging

Nuklearmedizinische Klinik im Klinikum rechts der Isar der Technischen Universität München

Hexokinase

no substrate for Phosphogluco-isomerase

Charged molecule → no passive diffusion

or cell membranepenetration

FURTHER GLYCOLYTICPATHWAY

no significant dephosphorylation

Imaging of Glucose MetabolismUptake and METABOLIC TRAPPING of [18F]FDG

OPO33-

F

OPO33-

F

Monitoring Therapy Response in Aggressive Lymphoma (DLBCL) by PET/CT

before therapy

after 6 x R-CHOP

Glucose Metabolism

Overall survival (intention-to-treat-analysis)Municon Trial

Median survival[95% CI] in months:

Metabolic Responder: Not reached

Metabolic Non-Responder:25.8 [19.4; 32.3]

Hazard ratio 2.13 [1.14-3.99]Log-rank p-value: p<0.015

Median follow-up: 28.0 monthsLancet Oncology 2007

Clinical Impact

Folkman J, N Engl J Med 1971

Therapeutic Targets

ANGIOGENESIS

OO

HOOH

NH

O

18F

OHNCO NH

NH

LysD-Phe

Asp

Gly

Arg

HO

OOO

HOOH

NH

O

18F

OHNCO NH

NH

LysD-Phe

Asp

Gly

Arg

HO

[18F]Galakto-RGDInhibitors of Angiogenesis

Therapeutic Target: Angiogenesis

Fusion of MR and RGD PET for Identification of Angiogenesis

C

FD

B

E

A

Avb3 Integrines

Combined analysis of αvβ3 expression, glucose metabolism and diffusivity with the Anima M3P software

T2w MRI ADC map and [18F]Galacto-RGD PET image fusion

DW-MRI: ADC map ADC map and [18F]FDG PETimage fusion

Cluster analysis of ADC and SUV of [18F]FDG PET

FDG

SU

V

ADC mm2/sec

Nekolla SG, van Marwick S 2010; Metz S, Beer AJ, JNM 2010;

MR/PET: translational research tool

Challenges for Clinical Application

Molecular imaging

Extraction of „Representative“ Signals Clinical Validation based on Outcome Clinical Acceptance and Reimbursement

• Biologic Specificity of Probes• Experimental Optimisation• Regulatory Hurdles• High cost to Clinical Product

Pathology of Alzheimer’s Disease

© National Institue of Aging

Clinical Translation

Mechanism of Amyloid Plaque ImagingTracers for Positron Emission Tomography (PET)

[11C]PIB

Vascularspace

NeuronGlial cell

Amyloid-Plaques

Molecular Imaging

Amyloid-Plaque Imaging (PET)

Glucose-metabolism

F-11 FDG30-60 min p.i.

AmyloidPlaque

ImagingC-11 6-0H-

BTA140-70 min

p.i.

M. Alzheimer Healthy ControlMCI

Surface projections, left lateral aspects

Amyloid-Plaques

Hypometabolism

Tailoring of TherapyEarlier Detectionof Disease

Longer Survival

Future of Molecular Imaging

Personalized Medicine

MR/PET München (TUM/LMU), Teil der DFG-Großgeräteinitiative

AcknowledgementsStephan NekollaSybille ZieglerAxel Martinez-MöllerSandra van Marwick

Hans Jürgen WesterSebastian FürstPetra Watzlowik

Gitti DzewasColetta KruschkeSylvia SchachoffPET- and Cyclotron-Team

Ambros BeerAlexander DrzezgaKen HerrmannMichael Souvatzoglou

Ernst J. RummenyMatthias EiberStephan Metz

Maximilian Reiser

Peter Bartenstein

Horst Kessler

Oliver Schnell

Markus NiemeyerMarion Kiechle