title: Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric cancer models in the pediatric preclinical testing program.
abstract: OBJECTIVE
  Inhibitors of PARP, an enzyme involved in base excision repair, have demonstrated single-agent activity against tumors deficient in homologous repair processes. Ewing sarcoma cells are also sensitive to PARP inhibitors, although the mechanism is not understood. Here, we evaluated the stereo-selective PARP inhibitor, talazoparib (BMN 673), combined with temozolomide or topotecan.
  
  
  METHODS
  Talazoparib was tested in vitro in combination with temozolomide (0.3-1,000 μmol/L) or topotecan (0.03-100 nmol/L) and in vivo at a dose of 0.1 mg/kg administered twice daily for 5 days combined with temozolomide (30 mg/kg/daily x 5; combination A) or 0.25 mg/kg administered twice daily for 5 days combined with temozolomide (12 mg/kg/daily x 5; combination B). Pharmacodynamic studies were undertaken after 1 or 5 days of treatment.
  
  
  RESULTS
  In vitro talazoparib potentiated the toxicity of temozolomide up to 85-fold, with marked potentiation in Ewing sarcoma and leukemia lines (30-50-fold). There was less potentiation for topotecan. In vivo, talazoparib potentiated the toxicity of temozolomide, and combination A and combination B represent the MTDs when combined with low-dose or high-dose talazoparib, respectively. Both combinations demonstrated significant synergism against 5 of 10 Ewing sarcoma xenografts. The combination demonstrated modest activity against most other xenograft models. Pharmacodynamic studies showed a treatment-induced complete loss of PARP only in tumor models sensitive to either talazoparib alone or talazoparib plus temozolomide.
  
  
  CONCLUSIONS
  The high level of activity observed for talazoparib plus temozolomide in Ewing sarcoma xenografts makes this an interesting combination to consider for pediatric evaluation.
authors.affiliation: Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland. Malcolm.Smith@nih.gov.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Texas Tech University Health Sciences Center, Lubbock, Texas.
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.affiliation: Texas Tech University Health Sciences Center, Lubbock, Texas.
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
authors.affiliation: A.I. duPont Hospital for Children, Wilmington, Delaware.
authors.forename: E Anders
authors.initials: EA
authors.lastname: Kolb
authors.affiliation: The Children's Hospital at Montefiore, Bronx, New York.
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia.
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
authors.affiliation: Duke University Medical Center, Durham, North Carolina.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.affiliation: Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine and Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania.
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.affiliation: St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Billups
authors.affiliation: Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Lyalin
authors.affiliation: Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Raushan T
authors.initials: RT
authors.lastname: Kurmasheva
authors.affiliation: Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D016513:Mice, SCID; D010793:Phthalazines / Q000008:administration & dosage*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012512:Sarcoma, Ewing / Q000473:pathology*; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003606:Dacarbazine; C586365:talazoparib; D000077204:Temozolomide