A Radiotracer Strategy to Quantify PARP-1 Expression In Vivo Provides a Biomarker That Can Enable Patient Selection for PARP Inhibitor Therapy.
Despite the availability of PARP inhibitors for cancer therapy, a biomarker to clearly stratify patients for selection of this treatment remains lacking. Here we describe a radiotracer-based method that addresses this issue, using the novel compound [(125)I] KX1: as a PARP-1-selective radiotracer that can accurately measure PARP-1 expression in vitro and in vivo The pharmacologic properties of the PARP radiotracer [(125)I] KX1: was characterized in multiple cell lines where single-agent sensitivity was correlated with [(125)I] KX1: binding to PARP-1. In vivo evaluation of [(125)I] KX1: verified in vitro results, validating PARP radiotracers to define PARP-1 enzyme expression as an in vivo biomarker. Notably, PARP-1 expression as quantified by [(125)I] KX1: correlated positively with the cytotoxic sensitivity of cell lines evaluated with PARP inhibitors. Overall, our results defined a novel technology with the potential to serve as a companion diagnostic to identify patients most likely to respond therapeutically to a PARP inhibitor. Cancer Res; 76(15); 4516-24. ©2016 AACR.
Division of Nuclear Medicine, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Mehran
M
Makvandi
Division of Nuclear Medicine, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Kuiying
K
Xu
Division of Nuclear Medicine, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Brian P
BP
Lieberman
Division of Nuclear Medicine, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Redmond-Craig
RC
Anderson
Division of Nuclear Medicine, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Samuel Sander
SS
Effron
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Harrison D
HD
Winters
Division of Nuclear Medicine, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Chenbo
C
Zeng
Division of Nuclear Medicine, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Elizabeth S
ES
McDonald
Division of Nuclear Medicine, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Daniel A
DA
Pryma
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Roger A
RA
Greenberg
Division of Nuclear Medicine, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. rmach@mail.med.upenn.edu.
Robert H
RH
Mach
D015415:Biomarkers; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis* / Q000378:metabolism
D015415:Biomarkers; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases