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Journal of Neuro-Oncology

, Volume 110, Issue 1, pp 37–48 | Cite as

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

  • J. Dawn WatersEmail author
  • Carlos Sanchez
  • Ayguen Sahin
  • Diahnn Futalan
  • David D. Gonda
  • Justin K. Scheer
  • Johnny Akers
  • Kamalakannan Palanichamy
  • Peter Waterman
  • Arnab Chakravarti
  • Ralph Weissleder
  • Brent Morse
  • Nick Marsh
  • Eric Furfine
  • Clark C. Chen
  • Irvith Carvajal
  • Bob S. CarterEmail author
Laboratory Investigation

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.

Keywords

Glioblastoma CT322 Vascular endothelial growth factor Xenograft Temozolomide AdnectinTM 

Notes

Acknowledgment

Grant Support: Adnexus, a Bristol-Myers Squibb R&D Company.

Conflict of interest

None

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Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • J. Dawn Waters
    • 1
    Email author
  • Carlos Sanchez
    • 2
  • Ayguen Sahin
    • 2
  • Diahnn Futalan
    • 1
  • David D. Gonda
    • 1
  • Justin K. Scheer
    • 1
  • Johnny Akers
    • 1
  • Kamalakannan Palanichamy
    • 3
  • Peter Waterman
    • 4
  • Arnab Chakravarti
    • 3
  • Ralph Weissleder
    • 4
  • Brent Morse
    • 5
  • Nick Marsh
    • 5
  • Eric Furfine
    • 5
  • Clark C. Chen
    • 1
  • Irvith Carvajal
    • 5
  • Bob S. Carter
    • 1
    Email author
  1. 1.Division of NeurosurgeryUniversity of California-San DiegoLa JollaUSA
  2. 2.Department of NeurosurgeryMGH-HMS Center for Nervous System RepairBostonUSA
  3. 3.Department of Radiation OncologyMassachusetts General HospitalBostonUSA
  4. 4.Center for Molecular ImagingMassachusetts General HospitalCharlestownUSA
  5. 5.AdnexusWalthamUSA

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