title: Preclinical evaluation of the PARP inhibitor, olaparib, in combination with cytotoxic chemotherapy in pediatric solid tumors.
abstract: BACKGROUND
  Poly(ADP-ribose) polymerase (PARP) signals DNA damage and facilitates DNA repair. PARP inhibitors are being evaluated in cancers with defective DNA repair mechanisms or in combination with cytotoxic therapy or radiation. We evaluated the PARP inhibitor, olaparib, in combination with chemotherapy using in vitro and in vivo pediatric solid tumor models.
  
  
  METHODS
  The IC50 of olaparib alone and in combination with cytotoxic agents was determined in 10 pediatric solid tumor cell lines. Synergy was assessed using the combination index of Chou-Talalay. Olaparib alone and in combination with topotecan/cyclophosphamide was evaluated in xenograft models of Ewing sarcoma (RD-ES) and neuroblastoma (NGP). PAR activity was evaluated in cell lines and tumor lysates.
  
  
  RESULTS
  Olaparib induced growth inhibition, median (range) IC50 = 3.6 (1-33.8) µM, and inhibited PAR activity in pediatric solid tumor cell lines. The addition of olaparib to DNA damaging agents resulted in additive to synergistic interactions. In RD-ES and NGP xenografts, olaparib inhibited PAR activity by 88-100% as a single agent and 100% when administered with cyclophosphamide/topotecan. Although the addition of olaparib did not antagonize the activity of cyclophosphamide/topotecan, clear evidence of synergy could not be demonstrated.
  
  
  CONCLUSIONS
  In pediatric solid tumor cell lines, clinically achievable concentrations of single agent olaparib caused growth inhibition. Although the in vitro data demonstrated synergistic efficacy of olaparib when added to the camptothecins and alkylating agents, synergy was not discernible in vivo. Clinical trials of PARP inhibitors in combination DNA damaging agents are necessary to establish the role of PARP inhibitors in childhood cancer.
authors.affiliation: Division of Pediatric Hematology/Oncology, Rainbow Babies & Children's Hospital, Cleveland, Ohio; Division of Clinical Pharmacology & Therapeutics, Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Robin E
authors.initials: RE
authors.lastname: Norris
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
authors.forename: Vu T
authors.initials: VT
authors.lastname: Nguyen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy*; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531550:olaparib
keywords: PARP inhibitor; olaparib
references.citation: Br J Cancer. 2010 Nov 9;103(10):1588-96
references.pmid: 20978505
references.citation: Lancet. 2010 Jul 24;376(9737):235-44
references.pmid: 20609467
references.citation: J Clin Oncol. 2010 Mar 10;28(8):1345-50
references.pmid: 20142599
references.citation: Pediatr Blood Cancer. 2010 Dec 1;55(6):1066-71
references.pmid: 20589656
references.citation: N Engl J Med. 2009 Jul 9;361(2):123-34
references.pmid: 19553641
references.citation: Blood. 2008 Feb 1;111(3):1078-84
references.pmid: 17975017
references.citation: J Pediatr Hematol Oncol. 2001 May;23(4):234-9
references.pmid: 11846302
references.citation: J Clin Oncol. 2010 Mar 10;28(8):1337-44
references.pmid: 20142589
references.citation: Mol Cancer Ther. 2009 Aug;8(8):2232-42
references.pmid: 19671751
references.citation: J Clin Oncol. 2010 Jul 20;28(21):3463-71
references.pmid: 20547984
references.citation: Breast Cancer Res Treat. 2012 Jul;134(2):649-59
references.pmid: 22678161
references.citation: Leukemia. 2010 Mar;24(3):491-9
references.pmid: 20072147
references.citation: Int J Cancer. 2006 Nov 1;119(9):2001-6
references.pmid: 16642469
references.citation: Clin Cancer Res. 2001 Feb;7(2):358-66
references.pmid: 11234891
references.citation: Clin Cancer Res. 2007 Mar 1;13(5):1383-8
references.pmid: 17332279
references.citation: Mol Cancer Ther. 2007 Mar;6(3):945-56
references.pmid: 17363489
references.citation: Pediatr Blood Cancer. 2009 Dec 15;53(7):1227-30
references.pmid: 19533660
references.citation: Anticancer Res. 2001 Mar-Apr;21(2B):1431-7
references.pmid: 11396227
references.citation: Ann Oncol. 2007 Sep;18(9):1500-5
references.pmid: 17698835
references.citation: J Clin Oncol. 2006 Aug 10;24(23):3799-808
references.pmid: 16896009
references.citation: Cancer Chemother Pharmacol. 2011 Dec;68(6):1469-75
references.pmid: 21484309
references.citation: Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5418-25
references.pmid: 17875772
references.citation: Cancer Res. 2012 Nov 1;72(21):5588-99
references.pmid: 23118055
references.citation: J Natl Cancer Inst. 2004 Jan 7;96(1):56-67
references.pmid: 14709739
references.citation: Clin Cancer Res. 2008 Jun 1;14(11):3248-53
references.pmid: 18519749
references.citation: Clin Cancer Res. 2009 Feb 15;15(4):1241-9
references.pmid: 19174487
references.citation: Pediatr Blood Cancer. 2011 Dec 15;57(7):1233-5
references.pmid: 21850675
references.citation: Blood. 1999 Aug 15;94(4):1192-200
references.pmid: 10438706
references.citation: Adv Enzyme Regul. 1984;22:27-55
references.pmid: 6382953
references.citation: Genes Chromosomes Cancer. 2005 Aug;43(4):390-403
references.pmid: 15892104
references.citation: Pediatr Blood Cancer. 2010 Aug;55(2):248-53
references.pmid: 20582981
references.citation: Oncogene. 2010 Sep 2;29(35):4938-46
references.pmid: 20562916
references.citation: J Clin Oncol. 2010 May 20;28(15):2512-9
references.pmid: 20406929
references.citation: Blood. 2009 Feb 26;113(9):1875-91
references.pmid: 18812465
references.citation: Lancet. 2010 Jul 24;376(9737):245-51
references.pmid: 20609468
references.citation: J Clin Oncol. 2013 Apr 20;31(12):1592-605
references.pmid: 23509311
references.citation: Gynecol Oncol. 2002 Apr;85(1):223-5
references.pmid: 11925151
references.citation: Mol Cancer Ther. 2005 Sep;4(9):1364-8
references.pmid: 16170028
references.citation: PLoS One. 2011;6(10):e26060
references.pmid: 22022506