Safe and effective sarcoma therapy through bispecific targeting of EGFR and uPAR

Antonella Borgatti, Joseph S. Koopmeiners, Aaron L. Sarver, Amber L. Winter, Kathleen Stuebner, Deborah Todhunter, Anthony E. Rizzardi, Jonathan C. Henriksen, Stephen Schmechel, Colleen L. Forster, Jong Hyuk Kim, Jerry Froelich, Jillian Walz, Michael S. Henson, Matthew Breen, Kerstin Lindblad-Toh, Felix Oh, Kristy Pilbeam, Jaime F. Modiano, Daniel A. Vallera

Research output: Contribution to journalArticle

7 Citations (Scopus)

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, 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 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 dosefinding, 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.

Original languageEnglish (US)
Pages (from-to)956-965
Number of pages10
JournalMolecular Cancer Therapeutics
Volume16
Issue number5
DOIs
StatePublished - May 1 2017

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Sarcoma
Dogs
Hemangiosarcoma
Therapeutics
Canidae
Pharmaceutical Preparations
Urokinase Plasminogen Activator Receptors
Exotoxins
Neoplasms
Urokinase-Type Plasminogen Activator
Residual Neoplasm
Pseudomonas
Epidermal Growth Factor
Doxorubicin
Carcinoma
Survival

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Safe and effective sarcoma therapy through bispecific targeting of EGFR and uPAR. / Borgatti, Antonella; Koopmeiners, Joseph S.; Sarver, Aaron L.; Winter, Amber L.; Stuebner, Kathleen; Todhunter, Deborah; Rizzardi, Anthony E.; Henriksen, Jonathan C.; Schmechel, Stephen; Forster, Colleen L.; Kim, Jong Hyuk; Froelich, Jerry; Walz, Jillian; Henson, Michael S.; Breen, Matthew; Lindblad-Toh, Kerstin; Oh, Felix; Pilbeam, Kristy; Modiano, Jaime F.; Vallera, Daniel A.

In: Molecular Cancer Therapeutics, Vol. 16, No. 5, 01.05.2017, p. 956-965.

Research output: Contribution to journalArticle

Borgatti, A, Koopmeiners, JS, Sarver, AL, Winter, AL, Stuebner, K, Todhunter, D, Rizzardi, AE, Henriksen, JC, Schmechel, S, Forster, CL, Kim, JH, Froelich, J, Walz, J, Henson, MS, Breen, M, Lindblad-Toh, K, Oh, F, Pilbeam, K, Modiano, JF & Vallera, DA 2017, 'Safe and effective sarcoma therapy through bispecific targeting of EGFR and uPAR', Molecular Cancer Therapeutics, vol. 16, no. 5, pp. 956-965. https://doi.org/10.1158/1535-7163.MCT-16-0637
Borgatti, Antonella ; Koopmeiners, Joseph S. ; Sarver, Aaron L. ; Winter, Amber L. ; Stuebner, Kathleen ; Todhunter, Deborah ; Rizzardi, Anthony E. ; Henriksen, Jonathan C. ; Schmechel, Stephen ; Forster, Colleen L. ; Kim, Jong Hyuk ; Froelich, Jerry ; Walz, Jillian ; Henson, Michael S. ; Breen, Matthew ; Lindblad-Toh, Kerstin ; Oh, Felix ; Pilbeam, Kristy ; Modiano, Jaime F. ; Vallera, Daniel A. / Safe and effective sarcoma therapy through bispecific targeting of EGFR and uPAR. In: Molecular Cancer Therapeutics. 2017 ; Vol. 16, No. 5. pp. 956-965.
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AU - Borgatti, Antonella

AU - Koopmeiners, Joseph S.

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AU - Stuebner, Kathleen

AU - Todhunter, Deborah

AU - Rizzardi, Anthony E.

AU - Henriksen, Jonathan C.

AU - Schmechel, Stephen

AU - Forster, Colleen L.

AU - Kim, Jong Hyuk

AU - Froelich, Jerry

AU - Walz, Jillian

AU - Henson, Michael S.

AU - Breen, Matthew

AU - Lindblad-Toh, Kerstin

AU - Oh, Felix

AU - Pilbeam, Kristy

AU - Modiano, Jaime F.

AU - Vallera, Daniel A.

PY - 2017/5/1

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N2 - 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 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 dosefinding, 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.

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