期刊
MOLECULAR CANCER THERAPEUTICS
卷 16, 期 5, 页码 956-965出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-16-0637
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资金
- Office of The Director, NIH [K01OD017242]
- National Canine Cancer Foundation [AB15MN-002]
- Masonic Cancer Center, University of Minnesota Sarcoma Translational Working Group
- AKC Canine Health Foundation [1889-G]
- U.S. Public Health Service Grant - NCI [R01 CA36725]
- NIAID
- DHHS
- Randy Shaver Cancer Research and Community Foundation
- Hyundai Scholar Senior Research Award
- Hyundai Hope on Wheels
- University of Minnesota Masonic Cancer Center
- GREYlong
- NIH Comprehensive Cancer Center Support Grant [P30 CA077598]
- NIH Clinical and Translational Science Award [UL1 TR000114]
- Sobiech Osteosarcoma Fund from the Children's Cancer Research Fund
- Angiosarcoma Awareness Foundation
- Alvin S. and June Perlman Chair in Animal Oncology at the University of Minnesota
Sarcomas differ from carcinomas in their mesenchymal origin. Therapeutic advancements have come slowly, so alternative drugs and models are urgently needed. These studies report a new drug for sarcomas that simultaneously targets both tumor and tumor neovasculature. eBAT is a bispecific angiotoxin consisting of truncated, deimmunized Pseudomonas exotoxin fused to EGF and the amino terminal fragment of urokinase. Here, we study the drug in an in vivo ontarget companion dog trial as eBAT effectively kills canine hemangiosarcoma and human sarcoma cells in vitro. Wereasoned the model has value due to the common occurrence of spontaneous sarcomas in dogs and a limited life-span allowing for rapid accrual and data collection. Splenectomized dogs with minimal residual disease were given one cycle of eBAT followed by adjuvant doxorubicin in an adaptive dose-finding, phase I-II study of 23 dogs with spontaneous, stage I-II, splenic hemangiosarcoma. eBAT improved 6-month survival from <40% in a comparison population to approximately 70% in dogs treated at a biologically active dose (50 mg/kg). Six dogs were long-term survivors, living >450 days. eBAT abated expected toxicity associated with EGFR targeting, a finding supported by mouse studies. Urokinase plasminogen activator receptor and EGFR are targets for human sarcomas, so thorough evaluation is crucial for validation of the dog model. Thus, we validated these markers for human sarcoma targeting in the study of 212 human and 97 canine sarcoma samples. Our results support further translation of eBAT for human patients with sarcomas and perhaps other EGFR-expressing malignancies. Mol Cancer Ther; (C) 2017 AACR.
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