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