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Safe and Effective ...
Safe and Effective Sarcoma Therapy through Bispecific Targeting of EGFR and uPAR.
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Borgatti, Antonella (författare)
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Koopmeiners, Joseph S (författare)
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Sarver, Aaron L (författare)
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Winter, Amber L (författare)
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Stuebner, Kathleen (författare)
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Todhunter, Deborah (författare)
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Rizzardi, Anthony E (författare)
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Henricksen, Jonathan C (författare)
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Schmechel, Stephen (författare)
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Forster, Colleen L (författare)
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Kim, Jong-Hyuk (författare)
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Froelich, Jerry (författare)
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Walz, Jillian (författare)
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Henson, Michael S (författare)
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Breen, Matthew (författare)
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- Lindblad-Toh, Kerstin (författare)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab,Broad Institute of MIT and Harvard, Cambridge, Massachusetts
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Oh, Felix (författare)
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Pilbeam, Kristy (författare)
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Modiano, Jaime F (författare)
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Vallera, Daniel A (författare)
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(creator_code:org_t)
- 2017
- 2017
- Engelska.
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Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 16:5, s. 956-965
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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 epidermal growth factor (EGF) and the amino terminal fragment (ATF) of urokinase. Here, we study the drug in an in vivo "ontarget" companion dog trial since eBAT effectively kills canine hemangiosarcoma (HSA) 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 HSA. eBAT improved 6-month survival from <40% in a comparison population to ~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 (uPAR) 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Borgatti, Antone ...
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Koopmeiners, Jos ...
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Sarver, Aaron L
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Winter, Amber L
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Stuebner, Kathle ...
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Todhunter, Debor ...
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visa fler...
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Rizzardi, Anthon ...
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Henricksen, Jona ...
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Schmechel, Steph ...
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Forster, Colleen ...
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Kim, Jong-Hyuk
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Froelich, Jerry
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Walz, Jillian
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Henson, Michael ...
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Breen, Matthew
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Lindblad-Toh, Ke ...
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Oh, Felix
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Pilbeam, Kristy
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Modiano, Jaime F
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Vallera, Daniel ...
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Cancer och onkol ...
- Artiklar i publikationen
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Molecular Cancer ...
- Av lärosätet
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Uppsala universitet