AAPM 2007 - MR Biomarkers - Jackson
AAPM 2007 – Imaging Symposium – Molecular Imaging Biomarkers
MR Biomarkers:
Current Applications and Unmet Needs
Edward F. Jackson, PhD
Department of Imaging Physics
MDACC MR Research
Rationale for Functional MR
• Both CT and MR provide exquisite views of anatomy and can be used to
assess changes in tumor volume/morphology.
• Anatomic imaging alone has significant limitations as morphological
changes can be slow to occur, particularly for cytostatic agents, and are
often nonspecific.
• Physiologic alterations precede morphologic changes and represent an
earlier measure of tumor response.
• Goal of functional and molecular imaging MR techniques:
– To obtain non-invasive biomarker information regarding changes in
microvascular parameters, biochemical distribution/concentration, cellularity,
tissue oxygenation, etc.
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
Imatinib mesylate (Gleevec) therapy of GIST
18FDG
SUV
Largest
Dimension (cm)
10.1
10.9
1.3
11.3
4.5
11.5
Gayed, Vu, Iyer, et al. J Nucl Med 45:17-21, 2004.
Applications to VEGFR Targeted Rx
MDACC MR Research
Stephens et al., Pharma Res EPUB, 2007
AAPM 2007 - MR Biomarkers - Jackson
Applications to HIF-1α Targeted Rx
MDACC MR Research
Stephens et al., Pharma Res EPUB, 2007
MRI: Anatomic Imaging
AAPM 2007 - MR Biomarkers - Jackson
Functional MR Techniques
• Assessing microvascular changes
– Dynamic contrast enhanced MRI (DCE-MRI) and dynamic susceptibility
change MRI (DSC-MRI)
• Assessing cell volume/density changes
– Quantitative diffusion MRI
• Assessing white matter changes
– Diffusion tensor imaging (DTI)
• Assessing changes in oxy- / deoxyhemoglobin ratio
– Blood oxygen level dependent (BOLD) MRI, susceptibility mapping
• Assessing biochemical changes
– In vivo MR spectroscopy
MDACC MR Research
Assessing Microvascular Changes
Goal:
1
:
Non-invasive assessment of
the effects of antiangiogenic /
antivascular therapy.
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
Paramagnetic contrast agent effects
100
r1 = 4.5
r2 = 5.5 mM-1 s-1
T2 (ms)
T1 (ms)
1000
mM-1 s-1
500
0
50
0
0
0.25
0.5
0.75
1
0
[Gd] (mM)
0.25
0.5
0.75
1
[Gd] (mM)
1
1
=
+ r1 [Gd ]
T2 T2,0
1
1
=
+ r1 [Gd ]
T1 T1,0
Effects of increasing Gd-DTPA concentration on T1 (left) and T2 (right) relaxation times in gray matter
(T1,0 = 1055 ms, T2,0 = 68 ms). Note the dominant effect on T1 relaxation times.
MDACC MR Research
Paramagnetic contrast agent effects
200
% Increase in Contrast
160
120
80
40
0
0
0.2
0.4
0.6
0.8
1
[Gd] (mM)
Percent increase in contrast for gray matter as a function of Gd-DTPA concentration
for a SE sequence with TR/TE = 400ms/18ms.
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
DCE-MRI Background
MDACC MR Research
DCE-MRI Background
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
Two Compartment Pharmacokinetic Model
Plasma
Flow
[GdDTPA] (mM)
3
2
Plasma
CP, vP
CL(t)
1
00
Measured
Endothelium
Ktrans
CP(t)
2
4
6
Time (min)
8
EES
CEES, ve
kep
10
Measured
CL(t) = vP CP(t) + CEES(t)
C EES (t ) = K trans
∫
t
0
C P (t ') e
− kep ( t − t ')
dt '
CP = [Gd] in plasma (mM) = Cb / (1-Hct)
CEES = [Gd] in extravascular, extracellular space (mM)
Ktrans = endothelial transfer constant (min-1)
kep = reflux rate (min-1)
vP = fractional plasma volume, ve = fractional EES volume
Standardized parameters as proposed by Tofts et al., J Magn Reson Imaging, 10:223-232, 1999.
MDACC MR Research
DCE-MRI Analysis
(
Signal intensity
data from tumor
and vascular ROIs
K trans ∫ CP ( t ')e
t
CL ( t ) =
)
(
S
⎡
−TR R1, 0
−TR R1 , 0
1 − cos α e
− cos α 1 − e
S0
1 ⎢
ln ⎢
ΔR1 =
S
−TR R1 , 0
−TR R1, 0
TR ⎢
1 − cos α e
1− e
−
⎢⎣
S0
(
− kep ( t −t ')
0
+ vP C P ( t )
1 − Hct
)
[Gd ] =
(
R1 − R1, 0
r1
) ⎤⎥
)
=
⎥ − R1, 0
⎥
⎥⎦
ΔR1
r1
Determine vP, Ktrans, and kep, from non-linear Marquardt-Levenberg fitting of
CL(t) and CP(t) data
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
High Resolution DCE-MRI
3D FSPGR w/Parallel
Imaging
20 5-mm sections every 4.5 s
0.94-mm in-plane resolution
Ktrans Parametric Maps
MDACC MR Research
PTK787/ZD222584 – Liver Mets
J Clin Oncol, 21:3955-64, 2003
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
PTK787/ZD222584 – Liver Mets
MDACC MR Research
J Clin Oncol, 21:3955-64, 2003
PTK787/ZD222584 – Liver Mets
MDACC MR Research
J Clin Oncol, 21:3955-64, 2003
AAPM 2007 - MR Biomarkers - Jackson
AG-013736 DCE-MRI Study
AG-013736 Trial (DCE-MRI and DCE-CT)
– Potent and selective inhibitor of VEGFR/PDGFR tyrosine kinases
– Preclinical activity in xenograft models (melanoma, colon, breast,
and lung)
– Multicenter Phase I study in solid tumors (MDACC, University of
Wisconsin, UCSF)
– Heterogeneous solid tumor patient population
MDACC MR Research
AG-013736 DCE-MRI Study
Ktrans Data at Baseline (left) and Day 2 (right)
McShane, Ashton, Jackson, et al., Proceedings of the ISMRM, p 154, 2004
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
AG-013736 DCE-MRI Study
N = 17
MDACC MR Research
Liu, Rugo, Wilding, et al., J Clin Oncol 23:5464, 2005.
Bevacizumab in IBC / LABC
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
Bevacizumab in IBC / LABC
MDACC MR Research
Wedam, Low, Yang, et al., J Clin Oncol 24:5, 2006
Bevacizumab in IBC / LABC
Baseline to End Cycle 1
% change
p-value
Baseline to End Cycle 4/7
% change
p-value
0.025
Ki67
NS
-35.1
MVD (CD31)
NS
NS
VEGF-A
NS
NS
p-VEGFR2 (Y996)
-69.2
0.025
-88.9
0.013
p-VEGFR2 (Y951)
-66.7
0.004
-76.4
0.009
VEGFR2
NS
TUNEL
128.9
0.0008
72.7
0.013
Ktrans
-34.4
0.003
-58.0
<0.0001
kep
-15.0
0.0007
-49.4
0.002
ve
-14.3
0.002
-20.4
0.020
NS
Wedam, Low, Yang, et al., J Clin Oncol 24:5, 2006
AAPM 2007 - MR Biomarkers - Jackson
DCE-MRI
Unmet needs for DCE-MR:
– Standardization of
• data acquisition strategies, and
• data analysis algorithms
– Quality control programs!
– Reproducibility/repeatability studies and comparisons with outcome and
tissue-based measures (multi-center)
– Anatomic coverage, temporal resolution, artifacts (especially motion),
arterial input function sampling, fast (reproducible) T1-measurement
techniques.
– Need for higher MW contrast agents
• Improved accuracy of blood volume and permeability-surface area measures
DCE-MRI Issues and Recommendations: Leach et al., Br J Cancer 92:1599, 2005
MDACC MR Research
DCE-MRI: Current Limitations
• Flow-limited case:
– Ktrans => EF --- the “extraction flow product”
• E = (1 - e-PS/F)
• Typically true for current FDA-approved small MW agents.
• Permeability-limited case:
– Ktrans => EF => PS
• Since E => PS / F
• Typically true for contrast agents with MW > ~35-45 kD.
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
Dual-Tracer DCE-MRI Technique
Signal Intensity
Slope ∝ Ktrans
ve
vP
Time
t1
t1 = time of
administration of
high MW agent
t2 = time of
administration of
low MW agent
t2
Weissleder et al., European J Cancer, 34:1448-1454, 1998.
MDACC MR Research
Baseline
Dual-Tracer DCE-MRI
Baseline
+ 20 min
PG-GdDTPA (short arrow)
& Magnevist (long arrow)
(MWPG-GdDTPA ~ 100 kDa*)
(MWMagnevist ~ 0.6 kDa)
Time (s)
*Provided by Chun Li, PhD
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
Dual Tracer DCE-MRI
60
Signal Intensity (au)
50
40
30
20
10
0
-10
0
200
400
600
800
T ime (s)
Central
P eripheral
First tracer: PG-GdDTPA (~100kD); Second tracer: GdDTPA (~0.6kD)
MDACC MR Research
Colo-205
Colo-205 Xenograft
IAUC
AUC
IAUC
AUC
PG-GdDTPA
parametric
images:
MagnevistTM
parametric
images:
MDACC MR Research
Colo-205
AAPM 2007 - MR Biomarkers - Jackson
DSC-MRI Techniques
• Dynamic susceptibility change (DSC) MRI techniques have
also been used to assess changes in regional blood flow.
• DSC-MRI uses T2- or T2*-weighted, high speed imaging
techniques, e.g., echo-planar imaging.
MDACC MR Research
Paramagnetic Contrast Agent Effects
100
r1 = 4.5
r2 = 5.5 mM-1 s-1
T2 (ms)
T1 (ms)
1000
mM-1 s-1
500
0
50
0
0
0.25
0.5
0.75
1
[Gd] (mM)
0
0.25
0.5
0.75
1
[Gd] (mM)
1
1
=
+ r1 [Gd ]
T2 T2,0
1
1
=
+ r1 [Gd ]
T1 T1,0
Effects of increasing Gd-DTPA concentration on T1 (left) and T2 (right) relaxation times in gray matter
(T1,0 = 1055 ms, T2,0 = 68 ms). Note the dominant effect on T1 relaxation times.
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
DSC-MRI Techniques
0.2 mmol/kg gadodiamide
bolus infusion at 5 cc/sec
SE-EPI
TE/TR = 80/1700 ms
30 cm FOV, 128x128 matrix
125 kHz, 5 mm slice, 1.5 mm gap
65 phases, 1:52 min
MDACC MR Research
DSC-MRI Techniques
Extract S(t)
Signal Intensity (Arb. Units)
350.0
τ
300.0
rCBV = ∫ ΔR2* (t ) dt
250.0
0
Inject
200.0
150.0
0.0
20.0
40.0
EPI Source Image
60.0
80.0
100.0
τ
120.0
∫ τ ΔR (t ) dt
*
2
Tim e (s)
ΔR2* = -1/TE ln[S(t)/S(0)]
rMTT =
0
*
2
0
Δ R2* (Arb. Units)
6.00
4.00
rCBF =
2.00
0.00
0.0
rCBV Map
τ
∫ ΔR (t ) dt
8.00
20.0
40.0
60.0
-2.00
Time (s)
MDACC MR Research
80.0
100.0
120.0
rCBV
rMTT
AAPM 2007 - MR Biomarkers - Jackson
DSC-MRI Techniques
T1-weighted Post-Gd
Computed rCBV Maps
MDACC MR Research
Assessing changes in 1H diffusion
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
Diffusion Imaging
Intracellular
space: Dintra
Extracellular
space: Dextra ~ 10 Dintra
Dmeasured =
DintraVintra + DextraVextra
Vintra + Vextra
MDACC MR Research
Diffusion Imaging
180o
90o
DAQ
G
δ
δ
Δ
δ⎞
⎛
b = γ 2 G2 δ 2 ⎜ Δ − ⎟
3⎠
⎝
S
= e−b D
S0
Stejskal, Tanner. J Chem Physics , 1965
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
Diffusion Imaging
Apparent diffusion coefficient (ADC) imaging
Acquisition of multiple sets of DWIs with varying b-values to allow
computation of ADC values on a pixel-by-pixel basis by linear regression
analysis of the signal attenuation equation, ln(S/S0) = -b ∗ ADC.
MDACC MR Research
Diffusion imaging - Ischemic injury
normal tissue
cells swell
lysis
Dnormal
D < Dnormal
D > Dnormal
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AAPM 2007 - MR Biomarkers - Jackson
Diffusion imaging in acute stroke
PDW
T2W
FLAIR
Diffusion
GE Medical Systems Applications Guide
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Diffusion Imaging Assessment of Therapy
MDACC MR Research
Moffat et al., PNAS 102:5524, 2005
AAPM 2007 - MR Biomarkers - Jackson
Diffusion Imaging Assessment of Therapy
Red: VR – increased ADC
Blue: VB – decreased ADC
Green: No change
VT = VR + VB
Hamstra et al., PNAS
102:16759, 2005
MDACC MR Research
Diffusion Imaging Assessment of Therapy
Overall Survival
PD
SD/PR
Kaplan-Meier plots
when stratified by VT
diffusion measures at
3 weeks into 7-week
fractionated regimen.
VT, threshold =
6.75%
TTP
VT = VR + VB
SD/PR
PD
MDACC MR Research
Hamstra et al., PNAS
102:16759, 2005
AAPM 2007 - MR Biomarkers - Jackson
3T Breast Diffusion Imaging
MDACC MR Research
Diffusion tensor imaging
⎡ Dxx
⎢
D = ⎢ Dxy
⎢
⎢⎣ Dxz
Dxy
D yy
D yz
Dxz ⎤
⎥
D yz ⎥
⎥
Dzz ⎥⎦
⎡λ1 0
D = E −1 ⎢⎢ 0 λ2
⎢⎣ 0 0
MDACC MR Research
0⎤
0 ⎥⎥ E
λ3 ⎥⎦
AAPM 2007 - MR Biomarkers - Jackson
Diffusion tensor imaging (DTI)
Using multiple diffusion encoding directions to determine the diffusion tensor terms,
the eigenvalue/eigenvector information can be used to characterize the anisotropy.
FA =
3
2
(λ1 -λ) 2 + (λ 2 -λ) 2 + (λ 3 -λ) 2
λ12 + λ 22 + λ 32
1.5T, b=1576 s/mm2, 6 directions
3.0T, b=1000 s/mm2, 15 directions
MDACC MR Research
Diffusion tensor imaging (DTI)
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
Multiparametric Assessment
• While each of the functional MR techniques presented thus far allows
the non-invasive assessment of treatment response, the combination of
the techniques may allow a much more comprehensive assessment.
• Combination of appropriate single modality imaging biomarkers with
those obtained from other modalities would be expected to provide even
more comprehensive assessment.
MDACC MR Research
AZD2171, Pan-VEGF Receptor
Tyrosine Kinase Inhibitor
Best-Responding Patient
Batchelor, Sorensen, et al.
Cancer Cell 11:83-95, 2007
AAPM 2007 - MR Biomarkers - Jackson
AZD2171, Pan-VEGF Receptor
Tyrosine Kinase Inhibitor
Worst-Responding Patient
Batchelor, Sorensen, et al.
Cancer Cell 11:83-95, 2007
Molecular MR Imaging
Primary types of imaging agents for MR
– T1 modifiers (typically based on paramagnetic atoms, e.g., Gd)
– T2* modifiers (typically ultrasmall superparamagnetic iron oxide
nanoparticles & aggregates)
– Chemical exchange saturation transfer (CEST) agents
– Hyperpolarized agents, e.g., 13C1-pyruvate.
MDACC MR Research
Shapiro et al., Magn Reson Imag 24:449, 2006
AAPM 2007 - MR Biomarkers - Jackson
T1 Modifiers – Paramagnetic Agents
100
T2 (ms)
T1 (ms)
1000
500
50
0
0
0
0.25
0.5
0.75
1
0
[Gd] (mM)
0.25
0.5
0.75
1
[Gd] (mM)
Effects of increasing Gd-DTPA concentration on T1 (left) and T2 (right) relaxation times
in gray matter (T1,0 = 1055 ms, T2,0 = 68 ms). Note the dominant effect on T1 relaxation
times (left) with an associated increase in signal intensity on T1-weighted images.
MDACC MR Research
T1 Modifiers - Necrosis
Polymeric DTPA-Gd-poly(L-glutamic acid) - provided by Chun Li, PhD
MW = 101.2 kD
Relaxivities @ 200 MHz: R1 = 8.9 mM-1 s-1; R2 = 21.5 mM-1 s-1
Untreated
120 equiv PGTXL/kg
M
Baseline
10 min
2 days
4 days
PG-DTPA-Gd
OCa-1
Jackson, Esparza-Coss, Wen et al., IJROBP, 2007
AAPM 2007 - MR Biomarkers - Jackson
T1 Modifiers - Necrosis
Untreated
x50
x200
120 equiv PGTXL/kg
Red: anti-mouse monoclonal antibody
directed against macrophages
Brown: avidin-HRP to biotinylated PGDTPG-Gd
x50
Blue: hematoxylin
x200
MDACC MR Research
T1 Modifiers - Necrosis
30
% of Tumor
25
20
15
10
5
0
D2
D3
D4
D7
D11
Timepoint
Treated
Control
Treatment: AMG-386
MDACC MR Research
Colo-205
AAPM 2007 - MR Biomarkers - Jackson
Molecular Imaging T1 Modifiers
Challenges for conventional T1
modifiers as molecular imaging
contrast agents: sensitivity.
β-galactosidase-activated Gd agent
Meade et al. - Northwestern
Nature Biotechnology, March 2000
Require high concentration (as
compared to nuclear medicine tracers
or optical agents), high T1 relaxivity,
or a means of signal amplification or
accumulation.
MDACC MR Research
Superparamagnetic Iron Oxides
Ultrasmall Superparamagnetic Iron Oxide (USPIO) nanoparticles
– ~4-6 nm diameter iron oxide crystalline core
– Low molecular weight dextran coating (prolong circulation time)
– Overall size: ~30 – 50 nm diameter
– Cleared by the reticuloendothelial system (macrophages / lymph
nodes) to liver and spleen and degraded.
– Accumulation of USPIOs causes signal loss on T2- and T2*-weighted
images due to signal dephasing resulting from intravoxel
inhomogeneity.
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
Baseline
24-hrs Post
USPIOs
Normal
Tumor
Micrometastases
Saokar et al., Abdom Imag, 2006
MDACC MR Research
Targeted USPIOs
Transferrin receptor-targeted monocrystalline ironoxide nanoparticles (MIONS)
Basilion et al. - MGH
Nature Medicine, March 2000
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
Targeted, bifunctional, iron oxides
Tumor Model: BT-20, expressing αvβ3 integrins.
Agent: cRGD-CLIO(Cy5.5)
OPTICAL
cRGD: cyclic arginine-glycine-aspartic acid,
which binds to integrins.
CLIO: cross-linked iron oxide nanoparticle
Baseline
MDACC MR Research
24-hrs post
Montet et al., Neoplasia,8:214, 2006
Hyperpolarized Agents
50 s
Injection of hyperpolarized 13C1pyruvate at time t = 0 s.
Data obtained every 3 s following
injection from rat muscle.
0s
Golman et al., PNAS, 103:11270, 2006
AAPM 2007 - MR Biomarkers - Jackson
Hyperpolarized Agents
Golman et al., PNAS, 103:11270, 2006
Unmet Needs - Techniques
• The implementation of “quantitative imaging” capabilities by the vendors
of MR equipment is driven by demand from the clinical users,
competition from other vendors, and whether or not such sequences and
analysis techniques lead to reimbursable procedures (FDA, CMS, etc.).
• There exists a need for standardized acquisition pulse sequences and
analysis techniques for MR “imaging biomarker” studies.
• Criteria for such standardized pulse sequences and analysis techniques
need to be developed.
• Validated phantoms and test data need to be available to users in order to
test new releases of pulse sequences and analysis software.
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
Unmet Needs – Techniques / QC
• Specific phantoms should be available to validate each vendor’s
acquisition techniques for the particular MR biomarker technique
(lesion morphology, perfusion, diffusion, MR spectroscopy, BOLD
assessment of hypoxia, etc.).
• In general, rigorous quality control programs in MR are relatively rare.
This can be problematic if multiple scanners are used to acquire study
data at one facility. For multicenter trials, this problem is clearly
exacerbated.
• Reproducibility/repeatability studies are lacking in several key areas.
MDACC MR Research
Summary Comments
• There can be no doubt that there is significant interest in non-invasive
imaging biomarkers for the (early) assessment of treatment response.
• MR, like other state-of-the-art imaging modalities, is poised to provide
such imaging biomarkers for both morphology and function.
• As with other modalities that provide means of early response to therapy
there is a tremendous opportunity for functional MR techniques to
contribute to drug development, treatment assessment, and to selection of
“patient specific therapies”.
• How will the imaging community respond to the challenge (and
paradigm shift) of quantitative imaging?
MDACC MR Research
AAPM 2007 - MR Biomarkers - Jackson
Some of the Pieces…
Imaging Response
Assessment Teams
(IRAT - NCI)
Uniform Protocols for
Imaging in Clinical Trials
(UPICT - ACR)
Imaging Equipment Vendors,
Pharma, & CROs
NCI / FDA /
Scientific Societies
Imaging Biomarker Quality
Control / Phantom
Development Groups
Imaging Scientists / Animal
Imaging Cores
Reference Image Database
to Evaluate Response
(RIDER) / caBIG Imaging
Workspace - NCI
(NCI/NIST/FDA; Inter-Society
and Inter-Agency WGs)
MDACC MR Research
Acknowledgments
•
•
•
•
•
•
•
•
•
Chun Li, Ph.D. and Xiaoxia Wen, M.S.
Qing Yuan, Ph.D.
Emilio Esparza-Coss, Ph.D.
Robert C. Orth, M.D., Ph.D.
Krista McAlee, R.T., Michelle Garcia, R.T., Tim Evans, R.T.
James Bankson, Ph.D.
Chaan Ng, M.D.
W.K. Alfred Yung, M.D., Charles Conrad, M.D., Vinay Puduvalli, M.D.
MDACC Small Animal Imaging Facility personnel
MDACC MR Research