Introduction: Small cell lung cancer (SCLC) has a dismal prognosis even after aggressive conventional therapy. Targeted therapy directed against vascular endothelial growth factor (VEGF) or its receptors (VEGFRs) has shown great promise in the clinic as part of the management of lung and other cancers. 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. In the current study we evaluated the therapeutic and antiangiogenic effects of cediranib (AZD2171), an orally available and highly potent selective inhibitor of all three VEGFR tyrosine kinases, alone and in combination with irinotecan (found in preliminary studies to be more active than other cytotoxic drugs used for SCLC in each model) in both orthotopic models. Methods: NCI-H187 or NCI-N417 SCLC cells were injected orthotopically into the lungs of mice. Subgroups of mice (n=5) were sacrificed weekly and assessed for the presence of lung tumors. After 2 weeks, when tumors were observed in all mice, the remaining animals (n=8/group) were randomized to treatment with cediranib (6 mg/kg/day orally); irinotecan (15 mg/kg/week ip); cediranib plus irinotecan; or vehicle. When control animals became moribund, all animals were sacrificed and assessed for lung tumor burden and lymphatic metastasis. Tumor and adjacent normal lung tissues were subjected to immunohistochemical analyses. Results: Cediranib therapy was well tolerated and highly effective in both orthotopic SCLC models and prevented mediastinal lymph node metastases in the NCI-H187 model. The addition of irinotecan to cediranib resulted in the near complete prevention of lung tumor growth and was superior to either treatment alone. In the NCI-H187 model, median tumor volume (mm3) was 620 (vehicle), 194 (paclitaxel; p < 0.05 versus vehicle), 108 (cediranib; p < 0.005 versus vehicle) and 28 (cediranib + paclitaxel; p < 0.005 versus vehicle). In the NCI-H417 model, median tumor volume (mm3) was 427 (vehicle), 200 (paclitaxel; p < 0.05 versus vehicle), 135 (cediranib; p < 0.005 versus vehicle) and 46 (cediranib + paclitaxel; p < 0.005 versus vehicle). Immunohistochemical studies of the lung tumors revealed that cediranib did not affect VEGF or VEGFR expression but inhibited VEGFR activation in the tumor vasculature. Lung tumor angiogenesis, as determined by microvessel density, was inhibited by treatment with cediranib alone and in combination with irinotecan. Cediranib therapy was associated with substantial tumor cell apoptosis in both models that was greater than that observed after irinotecan treatment alone. Conclusions: These data show that cediranib inhibits tumor angiogenesis and produces significant antitumor and antimetastatic effects in orthotopic human SCLC models. Combining cediranib with irinotecan enhanced the antitumor effects with a near complete suppression of tumor growth in the lung and metastasis to the mediastinum. These studies provide a strong basis for the design of clinical trials with cediranib in SCLC patients.
AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics-- Oct 22-26, 2007; San Francisco, CA