Potentiation of 177 Lu-octreotate peptide receptor radionuclide therapy of human neuroendocrine tumor cells by PARP inhibitor

// Nupur K. Purohit 1, 2, 3 , Rashmi G. Shah 1, 2, 3 , Samuel Adant 1, 2, 3, 4, 5 , Michael Hoepfner 6 , Girish M. Shah 1, 2, 3, * and Jean-Mathieu Beauregard 2, 4, 5, * 1 Department of Molecular Biology, Medical Biochemistry and Pathology, Universite Laval, Quebec City, Canada 2 Cancer Research Center, Universite Laval, Quebec City, Canada 3 Neurosciences and Oncology Branches of CHU de Quebec, Universite Laval Research Center, Quebec City, Canada 4 Department of Radiology and Nuclear Medicine, Universite Laval, Quebec City, Canada 5 Oncology Branch of CHU de Quebec, Universite Laval Research Center, Quebec City, Canada 6 Institute of Physiology, Charite-Universitatsmedizin Berlin, Berlin, Germany * Senior authorship Correspondence to: Jean-Mathieu Beauregard, email: jean-mathieu.beauregard@chudequebec.ca Keywords: peptide receptor radionuclide therapy; 177 Lu-octreotate; neuroendocrine tumors; PARP inhibitor; radiosensitization Received: November 08, 2017      Accepted: April 06, 2018      Published: May 15, 2018 ABSTRACT For patients with inoperable neuroendocrine tumors (NETs) expressing somatostatin receptors, peptide receptor radionuclide therapy (PRRT) with 177 Lu-[DOTA0-Tyr3]-octreotate ( 177 Lu-octreotate) is one of the most promising targeted therapeutic options but it rarely achieves cure. Therefore, different approaches are being tested to increase the efficacy of 177 Lu-octreotate PRRT in NET patients. Using the gastroenteropancreatic BON-1 and the bronchopulmonary NCI-H727 as NET cell models, here we report that pharmacological inhibitors of DNA repair-associated enzyme poly(ADP-ribose) polymerase-1 (PARPi) potentiate the cytotoxic effect of 177 Lu-octreotate on 2D monolayer and 3D spheroid models of these two types of NET cells. PARPi mediates this effect by enhancing 177 Lu-octreotate-induced cell cycle arrest and cell death. Thus, the use of PARPi may offer a novel option for improving the therapeutic efficacy of 177 Lu-octreotate PRRT of NETs.