Abstract 1800: The PARP inhibitor, rucaparib enhances the antitumor activity of 177Lu-DOTA-octreotate radionuclide therapy in preclinical models of neuroendocrine tumor
Authors: Cullinane Carleen , Waldeck Kelly , Eu Peter , Hicks Rodney J. 
Published: August 2015

Abstract
Purpose: Neuroendocrine tumors (NET) are a relatively rare, but heterogeneous group of tumors that arise predominantly in the gastrointestinal tract and bronchopulmonary system. While peptide receptor radionuclide therapy (PRRT) targeting somatostatin receptor 2 (SSTR2) has proved valuable in the treatment of NET, more effective clinical regimens are needed. In this study we investigated the efficacy of the combination of 177Lu-DOTA-octreotate (LuTate) PRRT and a poly (ADP-ribose) polymerase (PARP) inhibitor in well characterised preclinical NET models. Methods: A panel of seven cell lines with neuroendocrine features was characterised for SSTR2 expression, in vivo tumor growth properties, 68Ga-DOTA-octreotate (GaTate) uptake by positron emission tomography (PET) and sensitivity to LuTate. Representative tumor models were then selected to investigate the radiosensitizing potential of the PARP inhibitor, rucaparib when given in combination with LuTate. Results: Wide variation in SSTR2 mRNA and protein expression was observed between the various cell lines. Furthermore, immunohistochemical analysis revealed diffuse cytoplasmic expression of SSTR2 in vitro in contrast to strong cell membrane expression in vivo. Consistent with the in vivo cellular localisation, three tumor models demonstrated high tumor uptake of GaTate, an SSTR2 binding PET tracer used for the diagnosis and staging of NET. All three models responded to treatment with 20 MBq LuTate although the extent of the response was not predicted by SSTR2 expression or GaTate uptake. Treatment of A427-SSTR2 tumour bearing mice with two fortnightly cycles of 25 MBq Lutate in combination with rucaparib (15 mg/kg QD, IP) on days 1-5 of each cycle was well tolerated as assessed by the absence of any body weight loss. LuTate therapy alone induced tumour regression (56%) to day 32 after which the tumours began to regrow. Tumour regression in the combination treated group reached a maximum of 86% on day 35 (P&lt; 0.05 vs LuTate alone), after which the tumors began to regrow. The median conditional survival time of 93 days in the LuTate alone group was significantly increased to greater than 161 days in the combination treated group (P&lt; 0.01, Mantel Cox log rank test). Conclusions: Therapeutic regimens combining LuTate PRRT and PARP inhibitors as radiosensitizers may be an effective strategy for improving cellular responses in NET and warrants further clinical evaluation.
Citation Format: Carleen Cullinane, Kelly Waldeck, Peter Eu, Rodney J. Hicks. The PARP inhibitor, rucaparib enhances the antitumor activity of 177Lu-DOTA-octreotate radionuclide therapy in preclinical models of neuroendocrine tumor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1800. doi:10.1158/1538-7445.AM2015-1800