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, 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.

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

“…Some of these targeted toxins are bispecific, and their dual targeting ability confers greater binding affinity, increased killing ability, and a remarkable safety profile compared with monospecific counterparts . The potency and specificity of bispecific toxins have been demonstrated in vitro and in vivo against a variety of malignancies, including sarcomas, with good safety profiles …”

“…Recent work has focused on canine hemangiosarcoma . Unlike normal cells, hemangiosarcoma cells co‐express epidermal growth factor receptor (EGFR), and urokinase‐type plasminogen activator receptor (uPAR) .…”

“…Reportedly, canine hemangiosarcoma cells and hemangiosarcoma putative cancer stem cells express EGFR and uPAR and are highly sensitive to eBAT . Furthermore, eBAT was safe and effective in treating mice with cancer …”

“…One cycle of eBAT consisted of three treatments given on days 1, 3, and 5, with chemotherapy starting on day 21. A biologically active dose of 50 μg/kg was identified . Four dogs developed hypotension that resolved with medical management.…”

“…Side effects typically associated with other drugs that target EGFR were not observed, suggesting that simultaneous targeting of uPAR may have reduced the risk for toxicity. More than 70% of the dogs in the experimental group were alive 6 months following their diagnosis, compared with 38% of the dogs in the control group; six dogs treated with eBAT were alive 15 months after their diagnosis, compared with two of 28 dogs in the comparison group . Following these promising results, a second trial (SRCBST‐2) was performed to assess the inclusion of multiple cycles of eBAT administered with a reduced interval from doxorubicin chemotherapy.…”