ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors.

Abstract

PURPOSE:

Primary central nervous system (CNS) tumors represent a diverse group of tumor types with heterogeneous molecular mechanisms that underlie their formation and maintenance. CNS tumors depend on angiogenesis and often display increased activity of ErbB-associated pathways. Current nonspecific therapies frequently have poor efficacy in many of these tumor types, so there is a pressing need for the development of novel targeted therapies.

EXPERIMENTAL DESIGN:

ZD6474 is a novel, orally available low molecular weight inhibitor of the kinase activities associated with vascular endothelial growth factor receptor-2 and epidermal growth factor receptor. We hypothesized that ZD6474 may provide benefit in the treatment of several CNS tumor types.

RESULTS:

In mice bearing established s.c. tumor xenografts of CNS tumors (malignant glioma and ependymoma) or rhabdomyosarcoma, a limited course of ZD6474 treatment produced significant tumor growth delays and a high rate of partial tumor regression in most models examined. Mice with i.c. malignant glioma xenografts treated with ZD6474 experienced a significant prolongation of survival. Tumors from mice treated with ZD6474 displayed a lower proliferative index and disrupted tumor vascularity. Notably, some of these models are insensitive to low molecular weight kinase inhibitors targeting only vascular endothelial growth factor receptor-2 or epidermal growth factor receptor functions, suggesting that the combined disruption of both epidermal growth factor receptor and vascular endothelial growth factor receptor-2 activities may significantly increase tumor control.

CONCLUSIONS:

In conclusion, ZD6474 shows significant activity against xenograft models of several primary human CNS tumor types. Consideration for clinical development in this disease setting seems warranted.

• Authors: Jeremy N Rich, Sith Sathornsumetee, Stephen T Keir, Mark W Kieran, Andrea Laforme, Arja Kaipainen, Roger E McLendon, Michael W Graner, B K Ahmed Rasheed, Ling Wang, David A Reardon, Anderson J Ryan, Catherine Wheeler, Isaiah Dimery, Darell D Bigner, Henry S Friedman
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 22 Pg. 8145-57 (Nov 15 2005) ISSN: 1078-0432 [Print] United States
• PMID: 16299247 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ki-67 Antigen
• Piperidines
• Quinazolines
• ErbB Receptors
• Receptors, Vascular Endothelial Growth Factor
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• vandetanib

Topics

• Animals
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Central Nervous System Neoplasms (drug therapy, metabolism, pathology)
• Dose-Response Relationship, Drug
• Ependymoma (drug therapy, pathology)
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Glioma (drug therapy, pathology)
• Humans
• Immunohistochemistry
• Ki-67 Antigen (analysis)
• Mice
• Mice, Nude
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Neovascularization, Pathologic (metabolism, pathology, prevention & control)
• Phosphorylation (drug effects)
• Piperidines (pharmacology)
• Quinazolines (pharmacology)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors, metabolism)
• Xenograft Model Antitumor Assays