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
Kang, Zhigang; Goldstein, Seth D; Yu, Yunkai et al. (2015) Caspase-8 expression is predictive of tumour response to death receptor 5 agonist antibody in Ewing's sarcoma. Br J Cancer 113:894-901
Tang, Sai-Wen; Bilke, Sven; Cao, Liang et al. (2015) SLFN11 Is a Transcriptional Target of EWS-FLI1 and a Determinant of Drug Response in Ewing Sarcoma. Clin Cancer Res 21:4184-93
Kang, Z; Yu, Y; Zhu, Y J et al. (2014) Downregulation of IGFBP2 is associated with resistance to IGF1R therapy in rhabdomyosarcoma. Oncogene 33:5697-705
Kang, Zhigang; Sun, Shi-Yong; Cao, Liang (2012) Activating Death Receptor DR5 as a Therapeutic Strategy for Rhabdomyosarcoma. ISRN Oncol 2012:395952
Kang, Zhigang; Chen, Jun-Jie; Yu, Yunkai et al. (2011) Drozitumab, a human antibody to death receptor 5, has potent antitumor activity against rhabdomyosarcoma with the expression of caspase-8 predictive of response. Clin Cancer Res 17:3181-92
Zucali, Paolo A; Petrini, Iacopo; Lorenzi, Elena et al. (2010) Insulin-like growth factor-1 receptor and phosphorylated AKT-serine 473 expression in 132 resected thymomas and thymic carcinomas. Cancer 116:4686-95
Mayeenuddin, L H; Yu, Y; Kang, Z et al. (2010) Insulin-like growth factor 1 receptor antibody induces rhabdomyosarcoma cell death via a process involving AKT and Bcl-x(L). Oncogene 29:6367-77