title: Targeting the DNA repair pathway in Ewing sarcoma.
abstract: Ewing sarcoma (EWS) is a tumor of the bone and soft tissue that primarily affects adolescents and young adults. With current therapies, 70% of patients with localized disease survive, but patients with metastatic or recurrent disease have a poor outcome. We found that EWS cell lines are defective in DNA break repair and are sensitive to PARP inhibitors (PARPis). PARPi-induced cytotoxicity in EWS cells was 10- to 1,000-fold higher after administration of the DNA-damaging agents irinotecan or temozolomide. We developed an orthotopic EWS mouse model and performed pharmacokinetic and pharmacodynamic studies using three different PARPis that are in clinical development for pediatric cancer. Irinotecan administered on a low-dose, protracted schedule previously optimized for pediatric patients was an effective DNA-damaging agent when combined with PARPis; it was also better tolerated than combinations with temozolomide. Combining PARPis with irinotecan and temozolomide gave complete and durable responses in more than 80% of the mice.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Stewart
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Goshorn
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Cori
authors.initials: C
authors.lastname: Bradley
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Lyra M
authors.initials: LM
authors.lastname: Griffiths
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Benavente
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Nathaniel R
authors.initials: NR
authors.lastname: Twarog
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Miller
authors.affiliation: Preclinical Pharmacokinetics Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: William
authors.initials: W
authors.lastname: Caufield
authors.affiliation: Preclinical Pharmacokinetics Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Burgess B
authors.initials: BB
authors.lastname: Freeman
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Armita
authors.initials: A
authors.lastname: Bahrami
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Pappo
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Amos
authors.initials: A
authors.lastname: Loh
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Karlström
authors.affiliation: Animal Imaging Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Calabrese
authors.affiliation: Animal Imaging Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Brittney
authors.initials: B
authors.lastname: Gordon
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Tsurkan
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: M Jason
authors.initials: MJ
authors.lastname: Hatfield
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Potter
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Snyder
authors.affiliation: Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Thiagarajan
authors.affiliation: Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Abbas
authors.initials: A
authors.lastname: Shirinifard
authors.affiliation: Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Andras
authors.initials: A
authors.lastname: Sablauer
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: anang.shelat@stjude.org.
authors.forename: Anang A
authors.initials: AA
authors.lastname: Shelat
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: michael.dyer@stjude.org.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dyer
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D000077146:Irinotecan; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D010793:Phthalazines / Q000493:pharmacokinetics / Q000494:pharmacology; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000473:pathology*; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D000077146:Irinotecan; D003606:Dacarbazine; C586365:talazoparib; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib; D002166:Camptothecin; D000077204:Temozolomide