title: BO-1055, a novel DNA cross-linking agent with remarkable low myelotoxicity shows potent activity in sarcoma models.
abstract: DNA damaging agents cause rapid shrinkage of tumors and form the basis of chemotherapy for sarcomas despite significant toxicities. Drugs having superior efficacy and wider therapeutic windows are needed to improve patient outcomes. We used cell proliferation and apoptosis assays in sarcoma cell lines and benign cells; γ-H2AX expression, comet assay, immunoblot analyses and drug combination studies in vitro and in patient derived xenograft (PDX) models. BO-1055 caused apoptosis and cell death in a concentration and time dependent manner in sarcoma cell lines. BO-1055 had potent activity (submicromolar IC50) against Ewing sarcoma and rhabdomyosarcoma, intermediate activity in DSRCT (IC50 = 2-3μM) and very weak activity in osteosarcoma (IC50 >10μM) cell lines. BO-1055 exhibited a wide therapeutic window compared to other DNA damaging drugs. BO-1055 induced more DNA double strand breaks and γH2AX expression in cancer cells compared to benign cells. BO-1055 showed inhibition of tumor growth in A673 xenografts and caused tumor regression in cyclophosphamide resistant patient-derived Ewing sarcoma xenografts and A204 xenografts. Combination of BO-1055 and irinotecan demonstrated synergism in Ewing sarcoma PDX models. Potent activity on sarcoma cells and its relative lack of toxicity presents a strong rationale for further development of BO-1055 as a therapeutic agent.
authors.affiliation: Department of Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.|Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Srikanth R
authors.initials: SR
authors.lastname: Ambati
authors.affiliation: Department of Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Jae-Hung
authors.initials: JH
authors.lastname: Shieh
authors.affiliation: Department of Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Benet
authors.initials: B
authors.lastname: Pera
authors.affiliation: Department of Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Eloisi Caldas
authors.initials: EC
authors.lastname: Lopes
authors.affiliation: Department of Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Anisha
authors.initials: A
authors.lastname: Chaudhry
authors.affiliation: Department of Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Elissa W P
authors.initials: EW
authors.lastname: Wong
authors.affiliation: Department of Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Ashish
authors.initials: A
authors.lastname: Saxena
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Tsann-Long
authors.initials: TL
authors.lastname: Su
authors.affiliation: Department of Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Malcolm A S
authors.initials: MA
authors.lastname: Moore
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage; D004357:Drug Synergism; D045325:HCT116 Cells; D006801:Humans; D000077146:Irinotecan; D061986:MCF-7 Cells; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C582286:1-(3-((2-(dimethylamino)ethyl)carbamoyl)phenyl)-3-(4-(bis(2-chloroethyl)amino)phenyl)urea; D018906:Antineoplastic Agents, Alkylating; D009588:Nitrogen Mustard Compounds; D010671:Phenylurea Compounds; D000077146:Irinotecan; D002166:Camptothecin
keywords: DNA damage; DNA repair; Ewing sarcoma; PDX models; soft-tissue sarcomas