Safe and Effective Sarcoma Therapy through Bispecific Targeting of EGFR and uPAR
| Autor: | Jillian Zientek Walz, Anthony E. Rizzardi, Joseph S. Koopmeiners, Amber L. Winter, Matthew Breen, Colleen L. Forster, Jaime F. Modiano, Antonella Borgatti, Kathleen Stuebner, Jong Hyuk Kim, Deborah A. Todhunter, Daniel A. Vallera, Michael S. Henson, Stephen C. Schmechel, Jerry W. Froelich, Jonathan Henriksen, Felix Oh, Kristy Pilbeam, Aaron L. Sarver, Kerstin Lindblad-Toh |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Virulence Factors Bacterial Toxins Hemangiosarcoma Exotoxins Article Receptors Urokinase Plasminogen Activator Mice 03 medical and health sciences Dogs 0302 clinical medicine Cell Line Tumor medicine Animals Humans Doxorubicin Molecular Targeted Therapy Neoplasm Staging ADP Ribose Transferases Urokinase Epidermal Growth Factor Canine Sarcoma business.industry Cancer medicine.disease Canine Hemangiosarcoma Urokinase-Type Plasminogen Activator Minimal residual disease ErbB Receptors Urokinase receptor Disease Models Animal 030104 developmental biology Oncology 030220 oncology & carcinogenesis Immunology Cancer research Sarcoma business medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 16:956-965 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-16-0637 |
| Popis: | 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. We 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 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. |
| Databáze: | OpenAIRE |
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