Title: Imaging to Guide Early Drug Trials
1Imaging to Guide Early Drug Trials
-
- David A. Mankoff, MD, PhD
- Seattle Cancer Care Alliance
- University of Washington
- Seattle, WA
work supported by NIH Grants CA42045, CA72064,
MH63641, CA90771, S10 RR17229
2Cautions
- Most of the imaging methods presented are
considered investigational - Discussion of results and possible applications
is not a claim of clinical efficacy
3Imaging and Early Drug Trials
- Choosing the right patients
- Is the therapeutic target present?
- Choosing the right drug
- Does the drug reach the target?
- Getting the right result
- Is there a pharmacodynamic response?
4Early Drug Trials Why Imaging?
- Imaging samples the entire cancer
- Imaging is quantitative
- Imaging measures tumor heterogeneity
- Spatial
- Temporal (especially with Rx)
- Serial assay is feasible
- Complementary to in vitro assay
5Imaging and Early Drug Trials
- Choosing the right patients
- Is the therapeutic target present?
- Choosing the right drug
- Does the drug reach the target?
- Getting the right result
- Is there a pharmacodynamic response?
6F-18-Fluoroestradiol (FES) PET Estrogen
Receptor (ER) Imaging
FES
Estradiol
RBA (FES vs Estradiol)
ER 0.9
SHBG 0.8
(Kieswetter, J Nucl Med, 1984)
7FES Uptake Predicts Breast Cancer Response to
Hormonal Therapy
Post-Rx
Pre-Rx
Example 1
- Recurrent sternal lesion
- ER primary
- Recurrent Dz strongly FES
Excellent response after 6 wks Letrozole
FES
FDG
FDG
Example 2
- Newly Dxd met breast CA
- ER primary
- FES-negative bone mets
No response to several different hormonal Rxs
(Linden, J Clin Onc, 2006)
8FES Uptake Predicts Response of Advanced Breast
Cancer to Hormonal Therapy
LABC or Metastatic Br CA Primary Tamoxifen Rx
Recurrent or Metastatic Br CA Aromatase Inhibitor
Rx
FES SUV
Non-Responders
Responders
(Mortimer, J Clin Onc, 2001)
(Linden, J Clin Onc, 2006)
(P lt .01 for both)
9Imaging and Early Drug Trials
- Choosing the right patients
- Is the therapeutic target present?
- Choosing the right drug
- Does the drug reach the target?
- Getting the right result
- Is there a pharmacodynamic response?
10Resistance Due to Altered Drug Transport11C-Vera
pamil PET to Measure P-gp Drug Transport
Hypotheses
-P-gp limits drug transport
into the brain -Inhibiting P-gp will
increase brain transport
P-gp susceptible drug 11C-Verapamil
P-gp
P-gp susceptible drug 11C-Verapamil
x
inhibitor
(Hendrickse, Br j Pharmacol, 1998)
11Imaging P-gp Activity in Vivo in
Humans 11C-Verapamil images pre- and
post-cyclosporine (CSA)
88 /- 20 increase in verapamil AUC (N 12, P lt
.001)
(Sasongko, Clin Pharm Ther, 2005)
12Imaging and Early Drug Trials
- Choosing the right patients
- Is the therapeutic target present?
- Choosing the right drug
- Does the drug reach the target?
- Getting the right result
- Is there a pharmacodynamic response?
13FES PET Imaging Measures in Vivo Estrogen Binding
Antagonism by Tamoxifen
(thick sagittal planes)
Baseline
FDG
Glucose Metabolism
Estradiol Binding
FES
(Linden, SABCS, 2005)
14FES PET Measures Drug PharmacodynamicsStage IV
Breast Cancer Treated Using FulvestrantProgressiv
e Disease Despite Dose Increase
Pre-Rx
5 Months
1 month
Liver
SUV 7.4
SUV 3.2
SUV 3.1
Uterus
Post-Fulvestrant 250 mg qm
Post-Fulvestrant 500 mg qm
Pre-Fulvestrant
(Stable Dz, No Response)
(Dz Progression)
(FES PET, Coronal Slices)
(Linden, SABCS, 2005)
15Early Response of GIST to Imatinib Measured by
FDG PET
Annick Van Den Abbeele, Dana Farber, Boston
16Small Cell Lung Cancer PET Imaging Pre-and Post
One Cycle of Rx
7 days
(Shields, J Nucl Med, 1998)
17FLT Brain Tumor Imaging to Measure
ResponseKinetic Analysis (Muzi, J Nucl Med,
2006)
18F-Fluoro-L-thymidine (FLT)
Kinetic model
(Visvikis, Eur J Nucl Med Mol Imag, 2003 Muzi, J
Nucl Med, 2005)
18Special Considerations for Imaging and Early Drug
Trials
19Imaging Requirement for Biomarker
ImagingSimultaneously Localize and Characterize
Disease Sites
Functional/Anatomic Imaging
Functional Imaging Combinations
FES
FDG
PET/CT Fusion
FDG PET
Glucose Metabolism
Estradiol Binding
20Imaging Requirement for Biomarker Imaging Image
Acquisition and Quantitative Analysis
- Dynamic protocols
- Allows kinetic modeling
- Full range of analysis options
- But not for everyone
- Static protocols
- Clinically feasible, robust
- But only simple quantification possible
21Imaging and Early Drug Trials Summary
- Imaging complementary to tissue and blood assays
- Measure entire disease burden
- Quantitative
- Serial measures possible
- Guide early drug trials
- Measure target expression
- Measure drug delivery
- Measure early drug action
22Imaging and Early Drug Trials Collaborators
- UW Cancer PET Imaging
- Kenneth Krohn
- Janet Eary
- Jeanne Link
- Mark Muzi
- Joseph Rajendran
- Alex Spence
- Jash Unadkat
- SCCA/Breast Cancer
- Hannah Linden
- Robert Doot
- Lisa Dunnwald
- Brenda Kurland
- Lanell Peterson
- Erin Schubert
- Lavanya Sundarajan