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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Scientific Cores Intramural Research (ZIC)
Project #
1ZICBC011048-02
Application #
7970018
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2009
Total Cost
$181,367
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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