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. 2016 Aug 1;76(15):4516-24.
doi: 10.1158/0008-5472.CAN-16-0416. Epub 2016 Jun 3.

A Radiotracer Strategy to Quantify PARP-1 Expression In Vivo Provides a Biomarker That Can Enable Patient Selection for PARP Inhibitor Therapy

Mehran Makvandi  1 , Kuiying Xu  1 , Brian P Lieberman  1 , Redmond-Craig Anderson  1 , Samuel Sander Effron  1 , Harrison D Winters  2 , Chenbo Zeng  1 , Elizabeth S McDonald  1 , Daniel A Pryma  1 , Roger A Greenberg  2 , Robert H Mach  3
Affiliations

A Radiotracer Strategy to Quantify PARP-1 Expression In Vivo Provides a Biomarker That Can Enable Patient Selection for PARP Inhibitor Therapy

Mehran Makvandi et al. Cancer Res. .

Abstract

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.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Figures

Figure 1
Figure 1
A, competitive inhibition curves of [125I]KX1 with various PARPis in multiple cell lines. B, the structural similarities of KX1 and analogue PARPi rucaparib are illustrated.
Figure 2
Figure 2
A, saturation curves for [125I]KX1 in all cell lines evaluated are represented. B, [125I]KX1 Bmax (fmol/mg) values correlated with PARP-1 expression (r2 = 0.88), validating [125I]KX1 as a biomarker for PARP-1 expression. C, the comparison of PARP-1 expression versus activity as defined by [125I]KX1, PARP-1:H3, or PAR:H3, highlighting that [125I]KX1 binding corresponds with PARP-1 expression but not PAR expression. Cell lines listed in A from top to bottom represent bars in bar graphs in C from left to right. D, a representative Western blot analysis of PARP-1, PAR, and Histone H3 is shown.
Figure 3
Figure 3
A, in vitro growth inhibition curves for SNU-251, SKOV3, HCC1937, and MDA-MB-231 cells treated with either talazoparib or olaparib. Notice the leftward shift in ovarian cancer BRCA1-mutated cell line SNU-251 compared with SKOV3. B, growth inhibition curves for ovarian cancer and BRCA1-mutated/restored isogenic pair UWB1.289 and UWB1.289-BRCA1. Restoration of BRCA1 caused a significant decrease in sensitivity. C, growth inhibition assays carried out in MEF cell lines. No difference was observed in the absence of PARP2; however, drastic reductions in sensitivity were noticed in the MEF PARP1 KO−/− cell line.
Figure 4
Figure 4
Linear-regression plots correlating sensitivity to talazoparib (r2 = 0.84, P = 0.001) or olaparib (r2 = 0.77, P = 0.02) with PARP-1 expression. Resistant cell lines were not included in analysis and are outlined. Cell lines were excluded because of concentrations required for cytotoxic efficacy exceeded concentrations needed to occupy 90.9% of PARP-1 enzymes and therefore can be attributed to nonspecific effects.
Figure 5
Figure 5
A, total organ distribution of [125I] KX1 over the course of 6 hours (n = 4/time point). B, PARP-1 expression measured in HCC1937 and MDA-MB-231 tumors at time points up to 2 hours (n = 4/time point). C, ex vivo autoradiography of HCC1937 and MDA-MB-231 tumors at 2 hours. Olaparib-treated mice show a reduction in signal in HCC1937 but not in MDA-MB-231. D, in vivo competitive inhibition of [125I] KX1 using olaparib.*, signi of [125I] KX1 using olaparib cant change was measured in the organ.
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