A285

Lung cancer is the leading cause of cancer-related mortality with unsatisfactory overall response rates to chemotherapy. 75-80% of lung cancers are defined as non-small cell lung cancer (NSCLC). The inhibitor of apoptosis (IAP) proteins can block apoptosis or cell death caused by a variety of pro-apoptotic stimuli. Overexpression of IAP proteins causes chemoresistance and is a marker for poor prognosis in a variety of cancers. Antagonizing IAP proteins induces apoptosis in several human cancer cell lines. We tested here the efficacy of a novel small molecule IAP antagonist in an orthotopic model of lung cancer. Human NCI-H460 NSCLC cells (1 million cells in 20 μl PBS) were injected into the lung parenchyma in nu/nu nude mice. Ten days after cell injection, lung imaging was performed with an in-vivo micro-computed tomography (micro-CT) system to measure tumor volume for grouping. Mice were treated with vehicle or IAP antagonist at 100 mg/kg twice weekly by oral gavage (n=21 per group). Two weeks after treatment initiation, micro-CT imaging was repeated for tumor volume analysis. Lungs were removed and fixed in 10% buffered formalin. Total tumor area was quantified from 10 histological sections representative of 10 levels within the lungs. Micro-CT analysis showed no difference in tumor volume before treatment (10.3 ± 2.4 vs. 10.4 ± 2.6 mm3). There was a 47-fold increase in average tumor volume measured by micro-CT after 2 weeks treatment with vehicle. Treatment with IAP antagonist resulted in a 49% inhibition of tumor growth (p < 0.05) compared to vehicle-treated group. Intra-pulmonary cancer with poor differentiation was confirmed by histology. Quantitative analysis revealed that total tumor area was decreased by 48% in IAP antagonist-treated mice compared to vehicle controls (p < 0.05). There was a high correlation between tumor volume measured by micro-CT and total tumor area measured by histology (r=0.9394, p < 0.0001). The results demonstrated that human H460 NSCLC cells formed aggressive, rapidly growing tumors in the lung after orthotopic injection in nude mice. Treatment with the IAP antagonist as a single agent significantly inhibited growth of the orthotopic lung cancer as shown by both micro-CT imaging and histological analysis. These data suggest targeting IAP proteins in lung cancer with IAP antagonists may represent a useful new approach to improve the current management for this serious disease.

AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics-- Oct 22-26, 2007; San Francisco, CA