title: The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin.
abstract: Recent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing EWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents. Trabectedin is an antitumoral agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage. Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh disrupts the DDR machinery. Thus, given the impact and apparent specificity of both agents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity in ES, we decided to explore the activity of combining PARPinh and Trabectedin in in vitro and in vivo experiments. The combination of Olaparib and Trabectedin was found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, and the accumulation of G2/M. The drug combination also enhanced γH2AX intranuclear accumulation as a result of DNA damage induction, DNA fragmentation and global DDR deregulation, while EWSR1-FLI1 target expression remained unaffected. The effect of the drug combination was corroborated in a mouse xenograft model of ES and, more importantly, in two ES patient-derived xenograft (PDX) models in which the tumors showed complete regression. In conclusion, the combination of the two agents leads to a biologically significant deregulation of the DDR machinery that elicits relevant antitumor activity in preclinical models and might represent a promising therapeutic tool that should be further explored for translation to the clinical setting.
authors.affiliation: Laboratory of Molecular Pathology, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Seville, Spain.|Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer/Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Salamanca, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Ordóñez
authors.affiliation: Laboratory of Molecular Pathology, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Seville, Spain.|Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer/Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Ana Teresa
authors.initials: AT
authors.lastname: Amaral
authors.affiliation: Developmental Tumor Biology Laboratory, Preclinical Therapeutics and Drug Delivery Research Program, Hospital Sant Joan de Deu Barcelona, Spain.
authors.forename: Angel M
authors.initials: AM
authors.lastname: Carcaboso
authors.affiliation: Sarcoma Research Group, Laboratori d'Oncología Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Herrero-Martín
authors.affiliation: Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer/Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Salamanca, Spain.
authors.forename: María
authors.initials: M
authors.lastname: del Carmen García-Macías
authors.affiliation: Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer/Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Vicky
authors.initials: V
authors.lastname: Sevillano
authors.affiliation: Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer/Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Alonso
authors.affiliation: Developmental Tumor Biology Laboratory, Preclinical Therapeutics and Drug Delivery Research Program, Hospital Sant Joan de Deu Barcelona, Spain.
authors.forename: Guillem
authors.initials: G
authors.lastname: Pascual-Pasto
authors.affiliation: Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer/Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: San-Segundo
authors.affiliation: Developmental Tumor Biology Laboratory, Preclinical Therapeutics and Drug Delivery Research Program, Hospital Sant Joan de Deu Barcelona, Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: Vila-Ubach
authors.affiliation: Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer/Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Telmo
authors.initials: T
authors.lastname: Rodrigues
authors.affiliation: Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer/Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Fraile
authors.affiliation: Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer/Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Teodosio
authors.affiliation: Statistics and Operations Research Department, University of Valladolid, Spain.
authors.forename: Agustín
authors.initials: A
authors.lastname: Mayo-Iscar
authors.affiliation: Cell Biology and Pharmacogenomics Department, Pharmamar, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Aracil
authors.affiliation: Cell Biology and Pharmacogenomics Department, Pharmamar, Madrid, Spain.
authors.forename: Carlos María
authors.initials: CM
authors.lastname: Galmarini
authors.affiliation: Sarcoma Research Group, Laboratori d'Oncología Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Tirado
authors.affiliation: Developmental Tumor Biology Laboratory, Preclinical Therapeutics and Drug Delivery Research Program, Hospital Sant Joan de Deu Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Mora
authors.affiliation: Laboratory of Molecular Pathology, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Seville, Spain.|Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer/Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: de Álava
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002648:Child; D004249:DNA Damage; D004149:Dioxoles / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010793:Phthalazines / Q000008:administration & dosage / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D000077606:Trabectedin; D023041:Xenograft Model Antitumor Assays
chemical_list: D004149:Dioxoles; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; C531550:olaparib
keywords: DNA damage; Ewing sarcoma; PARP inhibitor; PDX models; trabectedin