Targeted therapy against VEGFR tyrosine kinase signaling by vandetanib inhibits tumor growth, angiogenesis, and progression in orthotopic human small cell lung cancer models
Authors: Kazuhisa Furutani, Ritsuko Komaki, Maria Korshunova, Anderson Ryan, Juliane Jurgensmeier, Roy Herbst, Michael OReilly
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

2495 

Introduction : Small cell lung cancer (SCLC) has a dismal prognosis even after aggressive conventional therapy. We have developed two distinct orthotopic models of human SCLC, which closely mimic clinical patterns of SCLC, in mice using the cell lines NCI-H187 and NCI-N417. The current study evaluated the therapeutic and antiangiogenic effects of vandetanib, an orally available and highly potent inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) tyrosine kinases, in both orthotopic models.    Methods : NCI-H187 or NCI-N417 SCLC cells were injected orthotopically into the lungs of mice. A subgroup of mice (n=5) were sacrificed after 8 days and lung tumors were observed in all of these mice. The remaining animals (n=10/group) were randomized to treatment with vandetanib (25 mg/kg/day orally) or vehicle control. When control animals showed signs of morbidity, all animals were sacrificed and assessed for lung tumor burden and lymphatic metastasis. Tumor and adjacent normal lung tissues were subjected to immunohistochemical analyses. Data were analyzed by Student's t test, Mann-Whitney U test, or Fisher’s exact probability test.    Results : In both orthotopic SCLC models, vandetanib therapy was well tolerated and highly effective in preventing lung tumor growth and mediastinal lymph node metastasis. In the NCI-H187 model, median lung weight and tumor volume were 322 mg and 109 mm3, respectively, after 32 days of vandetanib treatment versus 1,009 mg and 631 mm3 for vehicle control treated animals (p < 0.0005). In the NCI-N417 model, median lung weight and tumor volume were 555 mg and 226 mm3, respectively, after 35 days of vandetanib treatment versus 1,066 mg and 679 mm3 for vehicle control treated animals (p < 0.0005). Immunohistochemical studies of the lung tumors in both models revealed that the expression of VEGFR-2 was confined to the vasculature and that there was no detectable expression of EGFR or its ligands. Vandetanib did not affect VEGF or VEGFR-2 expression but potently inhibited VEGFR-2 activation in the tumor vasculature. Lung tumor angiogenesis, as determined by microvessel density, was inhibited by treatment with vandetanib in both models (p < 0.01). Vandetanib therapy was associated with an inhibition of lung tumor cell proliferation (p < 0.05) and resulted in marked endothelial cell and tumor cell apoptosis (p < 0.01) in both models as compared to vehicle treatment alone.    Conclusions : Vandetanib inhibits tumor angiogenesis and produces significant antitumor and antimetastatic effects in orthotopic human SCLC models. These data are consistent with inhibition of VEGFR-2 signaling by vandetanib, and provide a strong preclinical basis for the design of clinical trials with vandetanib in SCLC patients.