title: Potentiation of Peptide Receptor Radionuclide Therapy by the PARP Inhibitor Olaparib.
abstract: Metastases expressing tumor-specific receptors can be targeted and treated by binding of radiolabeled peptides (peptide receptor radionuclide therapy or PRRT). For example, patients with metastasized somatostatin receptor-positive neuroendocrine tumors (NETs) can be treated with radiolabeled somatostatin analogues, resulting in strongly increased progression-free survival and quality of life. There is nevertheless still room for improvement, as very few patients can be cured at this stage of disease. We aimed to specifically sensitize replicating tumor cells without further damage to healthy tissues. Thereto we investigated the DNA damaging effects of PRRT with the purpose to enhance these effects through modulation of the DNA damage response. Although PRRT induces DNA double strand breaks (DSBs), a larger fraction of the induced lesions are single strand breaks (expected to be similar to those induced by external beam radiotherapy) that require poly-[ADP-ribose]-polymerase 1 (PARP-1) activity for repair. If these breaks cannot be repaired, they will cause replication fork arrest and DSB formation during replication. Therefore, we used the PARP-1 inhibitor Olaparib to increase the number of cytotoxic DSBs. Here we show that this new combination strategy synergistically sensitized somatostatin receptor expressing cells to PRRT. We observed increased cell death and reduced cellular proliferation compared to the PRRT alone. The enhanced cell death was caused by increased numbers of DSBs that are repaired with remarkably slow kinetics, leading to genome instability. Furthermore, we validated the increased DSB induction after PARP inhibitor addition in the clinically relevant model of living human NET slices. We expect that this combined regimen can thus augment current PRRT outcomes.
authors: 1. Department of Molecular Genetics, Erasmus MC, Rotterdam, The Netherlands; 2. Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors: Julie
authors: J
authors: Nonnekens
authors: 1. Department of Molecular Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors: Melissa
authors: M
authors: van Kranenburg
authors: 3. Department of Radiation Oncology, Erasmus MC, Rotterdam, The Netherlands.
authors: Cecile E M T
authors: CE
authors: Beerens
authors: 4. Department of Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors: Mustafa
authors: M
authors: Suker
authors: 5. Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors: Michael
authors: M
authors: Doukas
authors: 4. Department of Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors: Casper H J
authors: CH
authors: van Eijck
authors: 2. Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors: Marion
authors: M
authors: de Jong
authors: 1. Department of Molecular Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors: Dik C
authors: DC
authors: van Gent
mesh_terms: D001859:Bone Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D042822:Genomic Instability; D006801:Humans; D008187:Lutetium; D012516:Osteosarcoma / Q000188:drug therapy* / Q000532:radiotherapy*; D010793:Phthalazines / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D011868:Radioisotopes; D011878:Radiotherapy / Q000379:methods; D017481:Receptors, Somatostatin / Q000187:drug effects
chemical_list: D004273:DNA, Neoplasm; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents; D011868:Radioisotopes; D017481:Receptors, Somatostatin; D008187:Lutetium; C531550:olaparib
keywords: 177Lu-DOTA-[Tyr3]octreotate; DNA damage response; Neuroendocrine tumors; PARP inhibitor; combination treatment; peptide receptor radionuclide therapy; somatostatin receptor