title: 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 (VEGFR-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.
authors.affiliation: Division of Neurosurgery, University of California-San Diego, La Jolla, CA 92093, USA. j.dawn.waters@gmail.com
authors.forename: J Dawn
authors.initials: JD
authors.lastname: Waters
authors.forename: Carlos
authors.initials: C
authors.lastname: Sanchez
authors.forename: Ayguen
authors.initials: A
authors.lastname: Sahin
authors.forename: Diahnn
authors.initials: D
authors.lastname: Futalan
authors.forename: David D
authors.initials: DD
authors.lastname: Gonda
authors.forename: Justin K
authors.initials: JK
authors.lastname: Scheer
authors.forename: Johnny
authors.initials: J
authors.lastname: Akers
authors.forename: Kamalakannan
authors.initials: K
authors.lastname: Palanichamy
authors.forename: Peter
authors.initials: P
authors.lastname: Waterman
authors.forename: Arnab
authors.initials: A
authors.lastname: Chakravarti
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Brent
authors.initials: B
authors.lastname: Morse
authors.forename: Nick
authors.initials: N
authors.lastname: Marsh
authors.forename: Eric
authors.initials: E
authors.lastname: Furfine
authors.forename: Clark C
authors.initials: CC
authors.lastname: Chen
authors.forename: Irvith
authors.initials: I
authors.lastname: Carvajal
authors.forename: Bob S
authors.initials: BS
authors.lastname: Carter
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy / Q000379:methods*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005353:Fibronectins / Q000494:pharmacology*; D005910:Glioma / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010446:Peptide Fragments / Q000494:pharmacology*; D000077204:Temozolomide; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: C549678:CT-322; D005353:Fibronectins; D010446:Peptide Fragments; D003606:Dacarbazine; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077204:Temozolomide