Objectives: The nuclear enzyme PARP-1 plays a central role in sensing DNA damage and facilitating repair. Tumors with BRCA1/2 mutations are highly dependent on PARP-1 as an alternative mechanism for DNA repair, and PARP inhibitors generate synthetic lethality in tumors with BRCA mutations, resulting in cell cycle arrest and apoptosis. Zhou et al. recently synthesized an 18F-labeled PARP-1 inhibitor (18F-FluorThanatrace) for PET, and demonstrated high specific tracer uptake in a xenograft model of breast cancer (Zhou, Bioorg Med Chem, 22:1700, 2014). The current study seeks to quantify the relationship between 18F-FluorThanatrace binding (both in vitro and on PET imaging of human tumor xenografts) and the level of constitutively active PARP-1, using multiple human breast cancer cell lines, including a BRCA1 defective line. Methods: BRCA1 defective HCC1937, triple negative MDA-MB-231, and luminal A MCF-7 human breast cancer lines were assessed for constitutive PARP-1 activity via a chemiluminescent ELISA assay for PAR and by Western blot. The same cell lines were incubated with 18F-FluorThanatrace over various time increments, and tracer uptake was assayed via a gamma counter. Specificity of tracer binding was verified via co-incubation with competitive inhibitor Olaparib, and specific tracer uptake was calculated as the difference between uptake with and without Olaparib. Specific tracer uptake was compared to levels of constitutive PARP-1 activity in all cell lines. In addition, HCC1937 and MDA-MB-231 xenograft tumor models were imaged via 18F-FluorThanatrace-PET/CT, and PET uptake was correlated with PARP-1 activity. Results: BRCA1-defective HCC1937 had higher constitutive PARP-1 activity than cell lines with intact BRCA1. In vitro levels of 18F-FluorThanatrace uptake correlated with constitutive PARP-1 activity across cell lines. In addition, 18F-FluorThanatrace measured by PET in xenograft breast cancer tumor models correlated with constitutive PARP-1 activity. Conclusions: Tumor uptake of 18F-FluorThanatrace, both in vitro and on PET imaging of xenograft tumor models, quantitatively reflects differences in PARP-1 activity across different breast cancer cell lines, including BRCA1 defective. This motivates further studies of 18F-FluorThanatrace as an in vivo measure of PARP-1 activity and possibly as a predictive marker for PARP-1 therapy in patients, including those with BRCA1/2 mutations. Citation Format: Edmonds CE, Lieberman BP, Xu K, Zeng C, Makvandi M, Li S, Hou C, Lee H, Greenberg RA, Mankoff DA, Mach RH. 18F-radiolabeled PARP-1 inhibitor uptake as a marker of PARP-1 activity in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-01-06.
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