Transcript Molecular Imaging 2017-1

Medical Imaging Workshop
Molecular Imaging
Marcelo Tatit Sapienza
INFIERI Summer School
Intelligent signal processing for FrontIER Research and Industry
Molecular Imaging
• Overview
• Imaging Modalities
• Clinical Applications – e.g. breast cancer
Molecular Imaging
MOLECULAR
BIOLOGY
In vivo
Imaging
visualisation, characterization and quantification of
normal / pathological biological processes at the
cellular and molecular level
MOLECULAR
BIOLOGY
Abnormal
cells with
pathological
phenotypes
Molecular
expression

Molecular paradigm
of diseases
Hallmarks of cancer – Cell 2000
Hanahan & Weinberg
Abnormal cells with
pathological phenotypes
Molecular expression
Probes / ligands may
be detected and allow
Therapy
with labeled
compounds
Diagnosis
Identification
of targets
for drugs
Therapy
planning
Therapy
response
Molecular Imaging
BASIC / PRECLINICAL RESEARCH
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Study of mechanisms of disease development and progression
Detection and activity of receptors and pathways
Pharmacokinetics / pharmacodynamics of target drugs
CLINICAL APPLICATIONS
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Understanding pathophysiological mechanisms
Diagnosis / Staging
Response to target drugs / individualized therapies
Translational research
• Molecular Target Identification
• Development of ligands
Preclinical • Experimental / preclinical evaluation
Clinical
• Image in humans  validation
• Approval by regulatory agencies
• Clinical application
Translational research
from BENCH
to
BEDSIDE
to
public health
Molecular Imaging
• Overview
• Imaging Modalities
• Clinical Applications – e.g. breast cancer
Imaging Modalities
Optical systems
Nuclear Medicine: PET /
SPECT
MRI
Ultrasonography
Computed tomography
Differences in
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Spatial resolution
Depth of evaluation
Ionizing / non-ionizing radiation
Available molecular markers or probes
Detection threshold
Imaging modalities
Willmann
Nature Reviews 2008
Imaging modalities
Optical Imaging: lower cost
 high-throughput screening for targets
low depth penetration  limited clinical translation
Nuclear Medicine: higher cost than optical
unlimited depth penetration  clinical translation
MRI:
high resolution and soft tissue contrast / cost and imaging time
US:
high spatial and temporal resolution / low cost / limited targets
CT:
high spatial resolution / no target specific imaging
Willmann Nature Reviews 2008
Spectrum of wavelenghts
Eletromagnetic radiation
MRI
Optical
CT / NM
Low energy
High energy
Infra red
Ultra violet
Optical Imaging
fluorescence and bioluminescence
Green fluorescent
protein
Reporter gene
(luciferase)
Near Infrared
fluorphores (NIR)
Prescher Current Opinion in Chemical Biology 2010
NM Radiopharmaceuticals
• radiolabeled molecules designed for in vivo application:
1. PHARMACEUTICAL= molecular structure determining the
fate of the compound within the organism
2. RADIO= radioactive nuclide responsible for a signal
detectable outside of the organism
e.g.
technetium-99m
half life 6 hours
gamma-ray photon 140 keV
Scintillation camara
Sorenson and Phelps,27 1987 W.B.Saunders
SPECT
Single Photon Emission Computed Tomography
Positron emitters
Nuclides
• F-18
• C-11
• N-13
• O-15 1
• Ga-68
• Rb-82
half life
110 min
20 min
10 min
2 min
68 min
1.3 min
Positron:
-Same mass as electron
-opposite electrical charge
-annihilation generates a pair of
gamma-ray photons – 180º
PET
Zanzonico Semin Nucl Med 2004
SPECT
PET
511 keV
140 keV
SPECT / CT
511 keV
PET / CT
PET
SPECT
PET > SPECT
•
Spatial resolution (human studies)
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Temporal resolution
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Sensitivity
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Cost
Molecular Imaging
Requirements
-
Imaging equipment
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Target selection
-
Development of imaging probe / tracer
Development of in vivo probes
< 5% of in vitro targets allow development of an in vivo tracer
• High TARGET concentration
– Affinity and specificity
– Absence of biological barriers (i.e. endothelium, blood brain barrier, ...)
– Stable labeling of compound
Development of in vivo probes
< 5% of in vitro targets allow development of an in vivo tracer
• High TARGET activity / concentration
– Affinity and specificity
– Absence of biological barriers (i.e. endothelium, blood brain barrier, ...)
– Stable labeling of compound
• Low BACKGROUND activity
– Non-specific accumulation,
– Circulating or interstitial activity
– Renal or hepatic elimination
Development of in vivo probes
< 5% of in vitro targets allow development of an in vivo tracer
• High TARGET activity / concentration
– Affinity and specificity
– Absence of biological barriers (i.e. endothelium, blood brain barrier, ...)
– Stable labeling of compound
• Low BACKGROUND activity
– Non-specific accumulation,
– Circulating or interstitial activity
– Renal or hepatic elimination
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Signal amplification
– Cell trapping
– Enzymatic conversion
– "Reporter" molecules: fluorescence, radiation, magnetic
EXAMPLE:
18FDG fluorodeoxyglucose = glucose analogue
• Transport (Glut)
• Phosphorylation (hexokinase)
• Metabolism
MOST TUMORS:
Increased Aerobic glycolysis (Warburg effect )
Phenotype common to most tumors
•Lower production of energy / mol
X
•NADPH Production - Synthesis
•Hypoxia and acidosis select cells resistant to
apoptosis
•Acid pH associated with invasion
Vander Heiden Understanding the Warburg Effect Science 2009
Hanahan & Weinberg
Cell 2011
Molecular Imaging
• Overview
• Imaging Modalities
• Clinical Applications – e.g. breast cancer
Breast cancer
•Brazil
Most incident in women
~ 50 /100,000
LOBULAR
57.120 new cases ( 2014 – INCA )
deaths: 13.345
( 2011 – SIM )
5 y survival ~ 60 %
DUCTAL
Breast cancer
Staging
- T 1 < 2 cm
AJCC Cancer Staging
Manual. 7th ed. 2010,
T2
2-5 cm T3
> 5 cm T4
thoracic wall / skin
- N0, 1 axillary I-II mobile, N2 axillary fixed or int.thoracic, N3 infra (III) / supraclavicular /
axillary+int. thoracic
- Metastases M0, M1
PROGNOSIS and CONDUCT
Therapy choices considers also :
- Clinical conditions, Age , Menopause, Histology of the tumor
- Hormone Receptors and HER2
Hormone and Growth Factor
Receptors expression variation
PREDICTIVE biomarker
= susceptibility of the tumor before indicating the therapy
BIOPSY:
TU hormone receptor ++  susceptible to treatment with drugs
that blocks either the estrogen receptors
or hormonal synthesis
Biomarker-driven
personalized cancer therapy
BUT…

Precision
medicine
Establishing genetic and molecular profile by
biopsy may not be sufficient:
Tumor
heterogeneity
Gerlinger,
Intratumor heterogeneity
NEJM 2012
18FES
– FLUOROESTRADIOL
 target = hormone receptor
FES
FDG
FDG posttherapy
PREDICTIVE biomarker in breast cancer
( indicates susceptibility to treatment )
Linden
JCO
2006
18FES
FES
– FLUORO ESTRADIOL
FDG
FDG posttherapy
Linden
JCO
2006
EARLY RESPONSE biomarker
= post-therapy prognosis
PET- FDG in the metabolic evaluation
after lymphoma chemotherapy
• Reduce or increase # chemotherapy cycles
• Change / add therapy
Kasamon JNM 2007
18F-FES
– FLUOROTHYMIDINE
 target = DNA synthesis
uptake after 1st cycle identifies responders ( p 0.001 ) - ( n= 15 )
EARLY RESPONSE biomarker
in breast cancer
Crippa F Eur J Nucl Med Mol Imaging 2015
18F-FES
– FLUORO THYMIDINE
EARLY RESPONSE biomarker in breast cancer
uptake after 1st cycle identifies responders ( p 0.001 ) - ( n= 15 )
Crippa F Eur J Nucl Med Mol Imaging 2015
Conclusion
• Molecular imaging is a multidiciplinary field in the
intersection of molecular biology and in vivo imaging
• Main pillars of MI are :
– Use of imaging modalities with different performances
– Development of probes/ligands detectable in vivo
• MI is part of translational research and may be
applied for biomarker-driven personalized therapy
( precision medicine )
Thank you !
[email protected]