title: Safe and Effective Sarcoma Therapy through Bispecific Targeting of EGFR and uPAR.
abstract: 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, deimmunizedPseudomonasexotoxin fused to EGF and the amino terminal fragment of urokinase. Here, we study the drug in anin vivo"ontarget" companion dog trial as eBAT effectively kills canine hemangiosarcoma and human sarcoma cellsin vitroWe reasoned the model has value due to the common occurrence of spontaneous sarcomas in dogs and a limited lifespan 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 μg/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; 16(5); 956-65. ©2017 AACR.
authors.affiliation: Animal Cancer Care and Research (ACCR) Program, University of Minnesota, St. Paul, Minnesota. borgatti@umn.edu.|Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Antonella
authors.initials: A
authors.lastname: Borgatti
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.|Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Koopmeiners
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Sarver
authors.affiliation: Clinical Investigation Center, College of Veterinary Medicine, St. Paul, Minnesota.
authors.forename: Amber L
authors.initials: AL
authors.lastname: Winter
authors.affiliation: Clinical Investigation Center, College of Veterinary Medicine, St. Paul, Minnesota.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Stuebner
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.|Department of Radiation Oncology, School of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Deborah
authors.initials: D
authors.lastname: Todhunter
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Rizzardi
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Henriksen
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Stephen
authors.initials: S
authors.lastname: Schmechel
authors.affiliation: BioNet Histology Research Laboratory, Academic Health Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Colleen L
authors.initials: CL
authors.lastname: Forster
authors.affiliation: Animal Cancer Care and Research (ACCR) Program, University of Minnesota, St. Paul, Minnesota.|Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jong-Hyuk
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Radiology, School of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jerry
authors.initials: J
authors.lastname: Froelich
authors.affiliation: Animal Cancer Care and Research (ACCR) Program, University of Minnesota, St. Paul, Minnesota.|Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota.
authors.forename: Jillian
authors.initials: J
authors.lastname: Walz
authors.affiliation: Animal Cancer Care and Research (ACCR) Program, University of Minnesota, St. Paul, Minnesota.|Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Henson
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, and Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, North Carolina.|Cancer Genetics Program, University of North Carolina Lineberger Comprehensive Cancer Center, Raleigh, North Carolina.
authors.forename: Matthew
authors.initials: M
authors.lastname: Breen
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.|Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
authors.affiliation: Department of Radiation Oncology, School of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Felix
authors.initials: F
authors.lastname: Oh
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Kristy
authors.initials: K
authors.lastname: Pilbeam
authors.affiliation: Animal Cancer Care and Research (ACCR) Program, University of Minnesota, St. Paul, Minnesota.|Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.|Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota.|Center for Immunology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jaime F
authors.initials: JF
authors.lastname: Modiano
authors.affiliation: Animal Cancer Care and Research (ACCR) Program, University of Minnesota, St. Paul, Minnesota.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.|Department of Radiation Oncology, School of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Vallera
mesh_terms: D036002:ADP Ribose Transferases / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics; D000818:Animals; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004285:Dogs; D004317:Doxorubicin / Q000008:administration & dosage; D004815:Epidermal Growth Factor / Q000737:chemistry / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005098:Exotoxins / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics; D006394:Hemangiosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D055293:Receptors, Urokinase Plasminogen Activator / Q000037:antagonists & inhibitors / Q000235:genetics*; D014568:Urokinase-Type Plasminogen Activator / Q000737:chemistry / Q000235:genetics; D037521:Virulence Factors / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D004317:Doxorubicin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D005098:Exotoxins; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C512478:EGFR protein, human