CT322, a VEGFR-2 antagonist, demonstrates anti-glioma efficacy in orthotopic brain tumor model as a single agent or in combination with temozolomide and radiation therapy

Abstract

Glioblastomas are among the most aggressive human cancers, and prognosis remains poor despite presently available therapies. Angiogenesis is a hallmark of glioblastoma, and the resultant vascularity is associated with poor prognosis. The proteins that mediate angiogenesis, including vascular endothelial growth factor (VEGF) signaling proteins, have emerged as attractive targets for therapeutic development. Since VEGF receptor-2 (VEG-FR-2) is thought to be the primary receptor mediating angiogenesis, direct inhibition of this receptor may produce an ideal therapeutic effect. In this context, we tested the therapeutic effect of CT322, a selective inhibitor of VEGFR-2. Using an intracranial murine xenograft model (U87-EGFRvIII-luciferase), we demonstrate that CT322 inhibited glioblastoma growth in vivo and prolonged survival. Of note, the anti-neoplastic effect of CT322 is augmented by the incorporation of temozolomide or temozolomide with radiation therapy. Immunohistochemical analysis of CT322 treated tumors revealed decreased CD31 staining, suggesting that the tumoricidal effect is mediated by inhibition of angiogenesis. These pre-clinical results provide the foundation to further understand long term response and tumor escape mechanisms to anti-angiogenic treatments on EGFR over-expressing glioblastomas.

Mutational and biophysical robustness in a prestabilized monobody

“…The Adnectin-anti-VEGFR2 monobody "CT-322" was the first of the Adnectin derivative of monobodies to reach clinical trials (41). Adnectin-anti-VEGFR2 showed potent efficacy with an antiangiogenic effect in preclinical models of pancreatic cancer (43), colorectal carcinoma and glioblastoma (41,44), brain tumors (45), and Ewing's sarcoma (46). Phase 1 clinical studies displayed clinical safety and acceptable pharmacokinetics to support phase 2 studies (47), although only some patients presented stable disease (48).…”

Apatinib Plus Temozolomide: An Effective Salvage Treatment for Recurrent Glioblastoma

“…In vitro , down-regulated VEGFR-2 results in decreased cell proliferation and higher sensitivity of glioma cells to temozolomide-induced G2 cell cycle arrest ( 21 ). In an intracranial murine xenograft model, inhibiting VEGFR-2 suppressed glioblastoma growth and prolonged mouse survival time, both of which were augmented by the incorporation of temozolomide ( 22 ).…”

Mutational and biophysical robustness in a pre-stabilized monobody

“…The Adnectin-anti-VEGFR2 monobody 'CT-322' was the first of the Adnectin derivative of monobodies to reach clinical trials (38). Adnectin-anti-VEGFR2 showed potent efficacy with an antiangiogenic effect in preclinical models of pancreatic cancer (40), colorectal carcinoma and glioblastoma (38,41), brain tumours (42), and Ewing's sarcoma (43). Phase 1 clinical studies displayed clinical safety and acceptable pharmacokinetics to support phase 2 studies (44), although only some patients presented stable disease (45).…”