Anti-Vascular Endothelial Growth Factor Therapies as a Novel Therapeutic Approach to Treating Neurofibromatosis-Related Tumors

作者：Wong Hon Kit; Lahdenranta Johanna; Kamoun Walid S; Chan Annie W; McClatchey Andrea I; Plotkin Scott R; Jain Rakesh K; di Tomaso Emmanuelle^*

来源：Cancer Research, 2010, 70(9): 3483-3493.

DOI：10.1158/0008-5472.CAN-09-3107

Patients with bilateral vestibular schwannomas associated with neurofibromatosis type 2 (NF2) experience significant morbidity such as complete hearing loss. We have recently shown that treatment with bevacizumab provided tumor stabilization and hearing recovery in a subset of NF2 patients with progressive disease. In the current study, we used two animal models to identify the mechanism of action of anti-vascular endothelial growth factor (VEGF) therapy in schwannomas. The human HEI193 and murine Nf2(-/-) cell lines were implanted between the pia and arachnoid meninges as well as in the sciatic nerve to mimic central and peripheral schwannomas. Mice were treated with bevacizumab (10 mg/kg/wk i.v.) or vandetanib (50 mg/kg/d orally) to block the VEGF pathway. Using intravital and confocal microscopy, together with whole-body imaging, we measured tumor growth delay, survival rate, as well as blood vessel structure and function at regular intervals. In both models, tumor vessel diameter, length/surface area density, and permeability were significantly reduced after treatment. After 2 weeks of treatment, necrosis in HEI193 tumors and apoptosis in Nf2(-/-) tumors were significantly increased, and the tumor growth rate decreased by an average of 50%. The survival of mice bearing intracranial schwannomas was extended by at least 50%. This study shows that anti-VEGF therapy normalizes the vasculature of schwannoma xenografts in nude mice and successfully controls the tumor growth, probably by reestablishing a natural balance between VEGF and semaphorin 3 signaling. Cancer Res; 70(9); 3483-93.

• 出版日期2010-5-1