Abstract 1397: VEGFR signaling inhibition by cediranib enhances the antitumor and anti-metastatic effects of chemotherapy and radiation in an orthotopic human lung cancer model

Abstract

Abstract Introduction: Cediranib (AZD2171, RECENTIN™) is a potent and orally available VEGF receptor signaling inhibitor in clinical development. This study evaluated the therapeutic efficacy and radiosensitizing effects of cediranib and paclitaxel in an orthotopic human lung cancer model that closely mimics clinical patterns of lung cancer progression. Methods: PC14PE6 human lung adenocarcinoma cells were injected into the left lungs of nude mice. Lung tumors were observed in all 5 mice sacrificed 14 days after tumor implant. The remaining mice were randomized (8/group) to receive vehicle (control), cediranib (3 mg/kg/day po), paclitaxel (200 µg/week ip), radiation to the left lung and mediastinum (20 Gy in 5 fractions over 2 weeks), or radiation with cediranib and/or paclitaxel. After 21 days, when control mice showed signs of becoming moribund, all mice were sacrificed and assessed for lung tumor burden and locoregional metastasis. Lung tumors and adjacent tissues were excised and analyzed by immunohistochemistry. Results: Radiation or cediranib monotherapy reduced median lung tumor volume by 80% (P=0.0016 vs control) and 82% (P=0.0011 vs control), respectively, significantly reduced mediastinal metastasis, and prevented pleural effusion. Paclitaxel reduced median tumor volume by 33% with a modest effect on lymphatic metastasis and pleural effusion. Cediranib substantially enhanced the antitumor and anti-metastatic effects of radiation therapy with a reduction in median primary tumor volume of 99.8% (P=0.0006) and left lung weight of 93% (P=0.0007) compared with control, with no evidence of mediastinal metastasis (P=0.0098). The effects of radiation therapy were only marginally improved by paclitaxel. Trimodality therapy with cediranib, paclitaxel and radiation resulted in the near complete prevention of lung tumor growth and metastasis. All treatments were well tolerated. Immunohistochemical analyses of lung tumors revealed that radiation or cediranib significantly reduced microvessel density and increased tumor and endothelial cell apoptosis and the antiangiogenic and apoptotic effects were substantially enhanced when these treatments were combined. Conclusions: In an orthotopic lung cancer model, targeted therapy against VEGFR by cediranib inhibits tumor growth and metastasis and enhances the effects of radiation therapy. The radiosensitizing effects of cediranib on lung tumors and their vasculature were superior to paclitaxel. Trimodality therapy with cediranib, paclitaxel, and radiation resulted in the near complete suppression of lung tumor growth and metastasis with markedly enhanced antiangiogenic and apoptotic effects. The combination of cediranib with radiation and chemotherapy is a potentially promising therapy for lung cancer and our data provide the basis for clinical trials in lung cancer 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 1397.