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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

Authors' Affiliations: Departments of ¹ Medicine, ² Neurobiology, ³ Surgery, ⁴ Pathology, and ⁵ Pediatrics, Duke University Medical Center, Durham, North Carolina; ⁶ Department of Pediatric Hematology-Oncology, Dana-Farber Cancer Institute; ⁷ Surgical Research Laboratory, Children's Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts; ⁸ Cancer Discovery, AstraZeneca, Macclesfield, Cheshire, United Kingdom; and ⁹ AstraZeneca, Wilmington, Delaware

Requests for reprints: Jeremy N. Rich, Division of Neurology, Duke University Medical Center, Box 2900, Durham, NC 27710. Phone: 919-681-1693; Fax: 919-684-6514; E-mail: rich0001{at}mc.duke.edu.

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.

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