Abstract 3716: Exploring the significance of PARP-1 expression for therapy and clinical PET/CT imaging of PARP-1 in ovarian cancer
Authors: Mehran Makvandi, Austin Pantel, Lauren E. Schwartz, Kuiying Xu, Chia-Ju Hsieh, Hyoung Kim, Shi-Hong Li, Robert Doot, Sharon Lee, Fiona Simpkins, Roger A. Greenberg, David A. Mankoff, Robert H. Mach, Lilie Lin
Journal: Cancer Research (2017)

Abstract Introduction: Poly(ADP-ribose) Polymerase 1 (PARP-1) is a multi-faceted enzyme that plays a significant role in DNA single-strand break and double-strand break repair. PARP inhibitors are emerging targeted therapeutics that inhibit the catalytic activity of PARP-1 and trap it on DNA producing poisonous lesions that result in cell death. While there is a vast body of pre-clinical and clinical data supporting the use of PARP inhibitors in cancers that express homologous recombination deficiencies like mutations within BRCA1/2 genes, there is an inadequate characterization of PARP-1 expression patterns in this context. Through pre-clinical studies we have explored the dynamics of PARP-1 expression in response to genotoxic stress, as well as the consequences of PARP-1 deletion for PARP inhibitor therapy in BRCA1 deficient ovarian cancer. In parallel, our group has performed the first clinical PET imaging study in epithelial ovarian cancer measuring PARP-1 in vivo using [18F]FluorThanatrace ([18F]FTT). Methods: CRISPR/Cas9 mediated PARP1 gene deletion was performed in BRCA1 deficient ovarian cancer cell lines. Next, in vitro cell viability assays were performed to evaluate the relative potency of clinically used PARP inhibitors and cisplatin. Following genotoxic stress the dynamics of PARP-1 expression were evaluated. In parallel clinical PET/CT imaging of PARP-1 was performed in epithelial ovarian cancer patients with correlative tissue histology. Results: Our studies indicate there is a spectrum of PARP-1 expression in epithelial ovarian cancer and in vitro BRCA1 mutants show higher PARP-1 expression compared to non-BRCA mutants. In addition, PARP-1 expression is required for PARP inhibitor efficacy in vitro and is either more significant or equal to BRCA1 mutational status. Also, high PARP-1 expression corresponded with platinum sensitivity in vitro. Furthermore, we observed PARP-1 expression increased in response to genotoxic insult relative to DNA damage measured by gH2AX. Lastly, our observations have been further supplemented by clinical [18F]FTT PET/CT images in ovarian cancer patients, which showed a spectrum of PARP-1 expression that corresponded with DNA damage measured by gH2AX. Conclusion: PARP-1 expression has the potential to identify functional DNA repair deficiencies and to provide a biomarker for assessing response to DNA damaging therapies. In complement, clinical PET imaging with [18F]FTT offers a novel technology to determine PARP-1 expression in ovarian cancer patients and warrants further study. Citation Format: Mehran Makvandi, Austin Pantel, Lauren E. Schwartz, Kuiying Xu, Chia-Ju Hsieh, Hyoung Kim, Shi-Hong Li, Robert Doot, Sharon Lee, Fiona Simpkins, Roger A. Greenberg, David A. Mankoff, Robert H. Mach, Lilie Lin. Exploring the significance of PARP-1 expression for therapy and clinical PET/CT imaging of PARP-1 in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3716. doi:10.1158/1538-7445.AM2017-3716