Abstract 3435: VEGF or VEGF and EGF receptor signaling inhibition by cediranib or vandetanib enhances the therapeutic effects of chemoradiation in an orthotopic small cell lung cancer model

Abstract

Abstract Background: Small cell lung cancer (SCLC) is associated with a poor prognosis and can recur even after chemoradiation therapy. In the current study, we evaluated the therapeutic, antiangiogenic, and radiosensitizing effects of cediranib (RECENTINTM; AZD2171), an orally available inhibitor of all 3 VEGF receptors, and vandetanib (ZACTIMATM; ZD6474), an orally available inhibitor of VEGFR and EGFR, in an orthotopic model of human SCLC that mimics patterns of SCLC progression. Methods: NCI-H187 human SCLC cells were injected into the left lungs of nude mice. To confirm tumor growth, 5 mice were sacrificed after 14 days. All had visible lung tumors and the remaining mice were randomized (8/group) to treatment with vehicle (control), cediranib (3 mg/kg/day po), vandetanib (25 mg/kg/day po), doublet chemotherapy (CDDP 8 mg/kg and CPT-11 15 mg/kg, weekly ip), radiation to the left lung and mediastinum (20 Gy in 5 fractions over 2 weeks), or vandetanib or cediranib in combination with radiation and/or chemotherapy. After 45 days, when controls showed signs of becoming moribund, all mice were sacrificed and assessed for lung tumor growth and metastasis. Lung tumors and adjacent tissues were analyzed by immunohistochemistry. Results: Treatment with vandetanib, cediranib, chemotherapy, or radiation inhibited lung tumor growth with a reduction in left lung weight by 56, 60, 87, or 86%, respectively, compared with control (P<0.03). The antitumor effects of radiation therapy combined with vandetanib or cediranib were similar with a reduction in left lung weight by 80 or 83%, respectively, compared with control (P<0.0001) with only a marginal impact upon mediastinal lymphatic metastasis. Trimodality therapy with chemoradiation and cediranib or vandetanib resulted in the near complete suppression of SCLC progression with no gross lung tumors observed in any of the 8 treated mice and lymphatic metastasis in only 1 mouse. All treatments were well tolerated. Immunohistochemical analyses of lung tumors revealed a significant reduction in microvessel density in all treatment groups. The antiangiogenic effects were substantially enhanced when cediranib or vandetanib was combined with chemotherapy and radiation. Conclusion: In an orthotopic SCLC model, targeted therapy against all 3 VEGFRs by cediranib or VEGFR and EGFR by vandetanib inhibited tumor growth and progression and enhanced the effects of radiation therapy. The radiosensitizing effects of cediranib or vandetanib in lung tumors and their vasculature was further improved by the addition of doublet chemotherapy, with the near complete suppression of lung tumor growth and mediastinal metastasis by trimodality therapy. The use of cediranib or vandetanib with chemoradiation therapy holds promise for the treatment of SCLC and our data provide the basis for clinical trials in SCLC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3435.