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Malignant Progression and Blockade of Angiogenesis in a Murine Transgenic Model of Neuroblastoma

Departments of ¹ Pediatrics, ² Neurology, ³ Neurological Surgery, ⁴ Brain Tumor Research Center, ⁵ Comprehensive Cancer Center, and ⁶ Pathology, University of California-San Francisco Medical School, San Francisco, California; ⁷ Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; ⁸ Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; and ⁹ Departments of Surgery and Cellular Biology, Harvard Medical School and Children's Hospital, Boston, Massachusetts

Requests for reprints: William A. Weiss, Department of Neurology, University of California-San Francisco, 533 Parnassus Avenue, Room U441O, San Francisco, CA 94143. Phone: 415-502-1694; Fax: 415-476-0133; E-mail: weiss{at}cgl.ucsf.edu.

Targeted expression of MYCN to the neural crest [under control of the rat tyrosine hydroxylase (TH) promoter] causes neuroblastoma in transgenic mice (TH-MYCN) and is a well-established model for this disease. Because high levels of MYCN are associated with enhanced tumor angiogenesis and poor clinical outcome in neuroblastoma, we serially characterized malignant progression, angiogenesis, and sensitivity to angiogenic blockade in tumors from these animals. Tumor cells were proliferative, secreted high levels of the angiogenic ligand vascular endothelial growth factor (VEGF), and recruited a complex vasculature expressing the angiogenic markers VEGF-R2, -SMA, and matrix metalloproteinases MMP-2 and MMP-9, all of which are also expressed in human disease. Treatment of established murine tumors with the angiogenesis inhibitor TNP-470 caused near-complete ablation, with reduced proliferation, enhanced apoptosis, and vasculature disruption. Because TNP-470 has been associated with neurotoxicity, we tested the recently described water-soluble HPMA copolymer–TNP-470 conjugate (caplostatin), which showed comparable efficacy and was well tolerated without weight loss or neurotoxicity as measured by rotarod testing. This study highlights the importance of angiogenesis inhibition in a spontaneous murine tumor with native tumor–microenvironment interactions, validates the use of mice transgenic for TH-MYCN as a model for therapy in this common pediatric tumor, and supports further clinical development of caplostatin as an antiangiogenic therapy in childhood neuroblastoma. [Cancer Res 2007;67(19):9435–42]

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