What if…Imaging could help guide treatment selection and determine whether a
treatment was working?
David Mankoff, MD, PhDGerd Muehllehner Professor & Vice-Chair for Research
Department of Radiology University of Pennsylvania
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What if imaging could help guide treatment selection and determine early on whether a treatment was working?
• Positron Emission Tomography (PET) – How it Works
• Measuring early response – bone metastases
• Imaging therapeutic targets
– Estrogen receptor (ER)
– PARP
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A Window on “In-the-Patient” Cancer Biology:Positron Emission Tomography (PET)Physics and Chemistry Meet Biology
Image of Tracer Concentration
Cyclotron: Isotope Production
18F*
Automated “Hot Cell”: Makes PET Tracer
18F-Fluorodeoxyglucose (FDG):a tracer of sugar metabolism
OOH
OH
OH
CH2OH
18F*
PET Tracer
PET Scanner: Takes Image of Tracer
Electron-Positron Interactions
FDG (Labeled Sugar) PET/CT Detects
Unsuspected Spread to the Chest (Mediastinum) Nodes
coronal whole
body image axial slice
Bone Scan & Bone Metastases:
Has there been a response to therapy?
Pre-TherapyPost-Therapy
(3 months)
FDG PET/CT: Has there been a response?
(answer = Yes!)
Pre-Therapy 4 weeks of Therapy
Sternum– max SUV 16.0 at baseline, 7.2 after 4 weeks
Treatment Targets for Breast Cancer:
The Estrogen Receptor (ER) and Endocrine Treatment
(Johnson and Dowsett, Nat Rev
Cancer 3:821, 2002)
ER - < 5%
ER + 50% - 75%
Endocrine Therapy
Response Rate:
Imaging Treatment Targets:18F-Fluoroestradiol (FES) PET Imaging of Estrogen
Receptor (ER) Expression in Breast Cancer
FDG FDGFES FES
Estradiol
Binding
Estradiol
Binding
Glucose
Metabolism
Glucose
Metabolism
Patient A
Biopsy = ER+
Patient B
Biopsy = ER-
Non-Homologous Repair (PARP)
Homologous Repair (BRCA Genes)
BRCA Gene LossXInhibit PARP X
Cell Death
PARP* Can Be an Important Target in BRCA-Deficient Cancer Cells
(*Poly-ADP Ribosylated Protein)
Increased PARP Levels May Indicate Susceptibility to
PARP Blocking Drugs
01
0
20 30 40 50 600
5
10
15
IF (RFU)
FT
T S
UV
MA
X
FTT versus Immunofluorescence
R2= 0.68
20 30 40 50 600
5
10
15
IF (RFU)
FD
G S
UV
MA
X
FDG versus Immunofluorescence
0.0 0.1 0.2 0.30
5
10
15
FDG versus [125I]KX1 Autoradiography
[125I]KX1 Uptake (µCi/mg)
FD
G S
UV
MA
X
0 5 10 150
5
10
15
FDG vs. FTT
FTT SUVMAX
FD
G S
UV
MA
X
R2= 0.0009
Fluorthanatrace ([18F]FTT ) Imaging PARP in Cancer
(Makvandi et al, J Clinical Investigation, 2018)
Imaging DNA Repair Targets:
FTT PET versus Tissue PARP FTT PET versus Tissue PARP
PRE-DRUG
[18F]FTT PET Shows That a PARP Inhibiting
Drug Blocks PARP Completely Guide PARP Inhibitor Dosing
Study PI: Fiona Simpkins (OBGYN)
POST-DRUG
What’s Next?
• Trial testing ability of FTT PET to predict response to PARP inhibiting drugs
– Ovarian Cancer: DOD Funding awarded
– Breast, Pancreatic, Prostate – in process
• New PARP-targeted therapy using therapeutic isotope (211At)
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Research Contributors
Radiochemistry/Cyclotron Facility/Radiology
• Robert Mach
• Mehran Makvandi
• Catherine Hou
• Chenbo Zeng
• Sharon Lee
• Shihong Li
• Christine Edmonds
PET Center/Radiology
• David Mankoff
• Dan Pryma
• Austin Pantel
• Robert Doot
• Mike Farwell
• Erin Schubert
• Jenny Cai
• Elizabeth McDonald
Radiation Oncology
• Lilie Lin
• Cam Koch
Cancer Biology, Ob/Gyn, Medical Oncology
• Roger Greenberg
• Fiona Simpkins
• Angie DeMichele
• Susan Domchek
• Payal Shah
• Amy Clark
Funding
– Basser Center
– DOE
– Susan G. Komen
– Marsha Rivkin Foundation
– Kaleidoscope of Hope
– ACC Paul Calabresi K12
– Radiology, Radiation Oncology