1. To understand the selective action of IGF1R antibodies against cancers: Our results revealed a high degree of variation of IGF1R levels in cancers. In addition, there is a direct correlation between the levels of IGF1R in cancer cells and the anti-proliferative response to anti-IGF1R antibodies. Cancer cells expressing elevated IGF1R (>30,000 copies per cells) are very sensitive to IGF1R antibody. 2. To provide a mechanism of action for anti-IGF1R agents: Our data suggest that tumor cells have a high degree of dependence on elevated IGF1R for maintaining high AKT signaling, both in vitro and in vivo. The inhibition of IGF1R with therapeutic antibodies resulted in a dramatic reduction of AKT signaling in tumor cells with elevated IGF1R. We identified the first model system in which IGF1R antibody induces rapid tumor cell death. Our results illustrate a unique mechanism of anti-IGF1R-induced cancer cell death. Our data further showed a dual function for IGF1R in tumor growth and survival. Moreover, the elevated IGF1R is pathogenic in our tumor model. 3. To identify and validate biomarkers predictive of responses to anti-IGF1R agents: Our results indicated a direct correlation between the IGF1R levels and the anti-proliferative activity of anti-IGF1R agents. Our data further suggests that elevated IGF1R predicts the response to IGF1R antibody-based therapeutics. 4. To enable the clinical investigation of biomarkers in correlative studies in clinical trials with anti-IGF1R agents: We have developed a range of immunoassays to support the clinical investigation of anti-IGF1R therapeutics, including a highly quantitative sandwich immunoassay capable of precise quantification of IGF1R in specimens, as well as a very practical immunohistochemistry assay capable of implementation with tissue slides from trial samples.
