Abstract
BackgroundVascular endothelial growth factor (VEGF) is a primary stimulant of angiogenesis under physiological and pathological conditions. Anti-VEGF therapy is a clinically proven strategy for the treatment of a variety of cancers including colon, breast, lung, and renal cell carcinoma. Since VEGFR2 is the dominant angiogenic signaling receptor, it has become an important target in the development of novel anti-angiogenic therapies. We have reported previously the development of an antagonistic VEGFR2 peptoid (GU40C4) that has promising anti-angiogenic activity in vitro and in vivo.MethodsIn the current study, we utilize a derivative of GU40C4, termed GU81 in therapy studies. GU81 was tested alone or in combination with doxorubicin for in vivo efficacy in the MMTV-PyMT transgenic model of breast cancer.ResultsThe derivative GU81 has increased in vitro efficacy compared to GU40C4. Single agent therapy (doxorubicin or GU81 alone) had no effect on tumor weight, histology, tumor fat content, or tumor growth index. However, GU81 is able to significantly to reduce total vascular area as a single agent. GU81 used in combination with doxorubicin significantly reduced tumor weight and growth index compared to all other treatment groups. Furthermore, treatment with combination therapy significantly arrested tumor progression at the premalignant stage, resulting in increased tumor fat content. Interestingly, treatment with GU81 alone increased tumor-VEGF levels and macrophage infiltration, an effect that was abrogated when used in combination with doxorubicin.ConclusionThis study demonstrates the VEGFR2 antagonist peptoid, GU81, enhances the anti-tumor activity of doxorubicin in spontaneous murine MMTV-PyMT breast tumors.
Highlights
Vascular endothelial growth factor (VEGF) is a primary stimulant of angiogenesis under physiological and pathological conditions
We first characterized the ability of GU81 to compete with GU40C4 for binding to both VEGFR1 and VEGFR2 (Figure 1B)
GU81 potently competes with GU40C4 for binding to both VEGFRs, indicating that these peptoids recognize the same epitope
Summary
Vascular endothelial growth factor (VEGF) is a primary stimulant of angiogenesis under physiological and pathological conditions. Since VEGFR2 is the dominant angiogenic signaling receptor, it has become an important target in the development of novel anti-angiogenic therapies. Angiogenesis, the development of new blood vessels from existing vessels, is required for tumor progression and metastasis [2]. For this reason, tumor angiogenesis has become an important target for cancer therapy [3,4]. Vascular endothelial growth factor (VEGF), a primary angiogenic growth factor in many tumor types, binds to and activates VEGFR1 and VEGFR2 [5]. As the angiogenic VEGF receptor, VEGFR2 has become a central target in developing anti-angiogenic therapies
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