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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.

Original publication

DOI

10.1158/1078-0432.CCR-05-0319

Type

Journal article

Journal

Clin Cancer Res

Publication Date

15/11/2005

Volume

11

Pages

8145 - 8157

Keywords

Animals, Cell Line, Tumor, Cell Movement, Cell Proliferation, Central Nervous System Neoplasms, Dose-Response Relationship, Drug, Ependymoma, ErbB Receptors, Glioma, Humans, Immunohistochemistry, Ki-67 Antigen, Mice, Mice, Nude, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Neovascularization, Pathologic, Phosphorylation, Piperidines, Quinazolines, Receptors, Vascular Endothelial Growth Factor, Xenograft Model Antitumor Assays