Work

BO-1055, a novel DNA cross-linking agent with remarkable low myelotoxicity shows potent activity in sarcoma models

Year: 2016

Type: article

Abstract: // Srikanth R. Ambati 1,2 , Jae-Hung Shieh 1 , Benet Pera 1 , Eloisi Caldas Lopes 1 , Anisha Chaudhry 1 , Elissa W.P. Wong 1 , Ashish Saxena 1 , Tsann-Long Su 3 and Malcolm A.S. Moore 1 1 Department of Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, United States 2 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, United States 3 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan Correspondence to: Srikanth R. Ambati, email: // Keywords : Ewing sarcoma, soft-tissue sarcomas, DNA damage, DNA repair, PDX models Received : May 05, 2016 Accepted : May 14, 2016 Published : May 29, 2016 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.9657