Abstract A054: Real-time imaging of PARP-1 in ovarian cancer

Abstract

Abstract Introduction: Poly(ADP-ribose) polymerase inhibitors (PARPi) are emerging targeted therapeutics for the treatment of ovarian cancer and were initially recognized to work in BRCA1/2 mutation carriers. However, a recent clinical trial showed that all platinum-sensitive ovarian cancer patients benefited from the second-generation PARPi, niraparib, suggesting newer biomarkers would be useful for patient selection. Second-generation PARPi are more effective at trapping PARP-1 on DNA lesions and have improved cellular lethality compared to first-generation PARPi. Due to the critical role of PARP-1 in the PARP trapping hypothesis, PARP-1 expression has the potential to serve as a biomarker for the appropriate selection of ovarian cancer patients for PARPi therapy. In this work, we present the noninvasive real-time imaging of PARP-1 through positron emission tomography (PET) with a radiolabeled PARPi, [18F]FluorThanatrace ([18F]FTT) in primary and disseminated ovarian cancer as a novel approach to quantify PARP-1 expression and monitor patients on PARP inhibitor therapy. Methods: Patients underwent [18F]FTT PET/CT imaging on a whole-body PET/CT scanner (Phillips Medical System, Netherlands). Image reconstruction was carried out using standard procedures. Images were interpreted by trained nuclear medicine physicians who first located lesions on a contemporaneous clinical [18F]FDG study and then found the corresponding lesion on the [18F]FTT image and recorded the maximum standard-uptake-value (SUV). Immunohistochemistry using clinical adjacent tumor sections was performed for hematoxylin and eosin (HE) and biomarkers including PARP-1, γH2AX, p-53, LCA, and AE1-3. Furthermore, PARP-1 was evaluated by both fluorescent IHC and [125I]KX1 autoradiography on adjacent sections and was correlated with maximum SUV of [18F]FTT for known sites of disease. Results: We enrolled 10 EOC patients, 7 of whom underwent [18F]FTT imaging in addition to standard clinical management including surgical debulking or biopsy. A total of 14 tissue specimens were available from the 10 patients and were used for in vitro assays including PARP-1 fluorescent IHC and [125I]KX1 autoradiography. We observed a spectrum of [18F]FTT uptake. Maximum SUV ranged from as low as 2 (background) to as high as 12.1. In addition, we found a correlation (r2 = 0.74, 0.79) between PARP-1 fluorescent IHC and [18F]FTT PET imaging, as well as with FTT analogue [125I]KX1 autoradiography. No correlations were found between PARP-1 fluorescent IHC or [18F]FTT and [18F]FDG. Conclusion: We found that uptake of [18F]FTT positively correlated with PARP-1 expression by fluorescent IHC. This provides early proof of concept of [18F]FTT as a clinical biomarker of PARP-1 expression in primary and disseminated disease. The spectrum of PARP-1 expression measured by [18F]FTT ranged from maximum SUV of 2 to 12, providing preliminary evidence for differences in PARP-1 expression affecting PARPi tumor targeting. Studies are now under way evaluating [18F]FTT as a biomarker to assess PARPi drug target engagement with the goal of entering multicenter clinical trials in ovarian, breast, and prostate cancer. Citation Format: Mehran Makvandi, Austin Pantel, Lauren Schwartz, Robert Doot, Fiona Simpkins, David A. Mankoff, Robert H. Mach, Lilie Lin. Real-time imaging of PARP-1 in ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A054.