Our previous results revealed a high degree of variation of IGF1R levels in cancers (Cao et al., Cancer Res. 68: 8039-48, 2008) showed 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 were very sensitive to IGF1R antibody. Our data suggested that tumor cells had 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. In our current study, we identified a model system in which IGF1R antibody selectively induced rapid tumor cell death in vitro and in vivo. Our results illustrate the mechanism of anti-IGF1R-induced cancer cell death mediated via AKT and BclxL. Tumor cells without elevated Bcl2 had a greater degree of dependence on IGF1R and AKT signaling, and thus, more susceptible to anti-IGF1R induced cell death. Our data further showed a dual function for IGF1R in tumor growth and survival. This work results in a paper in press for oncogene (Mayeenuddin et al., Oncogene. 2010). It wascited at the Platinum Publications (12/2010) and featured at In the Journal by CCR, NCI(9/2010). To identify novel agents with selective activity against sarcoma and biomarkers predictive of responses, we investigated a death receptor DR5 targeted antibody drozitumab in working with Genentech. We show that DR5, but not DR4, persisted at high levels and on the surface of all rhabdomyosarcoma (RMS) cells. DR5 antibody drozitumab was effective in vitro against the majority of RMS cell lines. There was a strong correlation between caspase-8 expression and the sensitivity to drozitumab, which induced the rapid assembly of the death-induced signaling complex and the cleavage of caspase-8 only in sensitive cells. More importantly, caspase-8 catalytic activity was both necessary and sufficient for mediating the sensitivity to drozitumab. Furthermore, drozitumab had potent antitumor activity against established RMS xenografts with a specificity predicted from the in vitro analysis and with tumor-free status in half of the treated mice. Our study provides the first preclinical evaluation of the potency and selectivity of a death receptor antibody in RMS. Drozitumab is effective, in vitro, against the majority of RMS cell lines that express caspase-8 and, in vivo, may provide long-term control of RMS. The work was published in Clin Cancer Res (Kang et al., 2011). Our wrok led to the initiation of dissucions to develop a CRADA with a major pharmaceutical company. We are pursuing the possibility of bringing a DR5 targeted agent to NCI for clinical investigations. Our investigations into novel agents targeting sarcoma and selectivity of these agents are being translated into predictive biomarkers for clinical studies and agents for clinical trials.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Scientific Cores Intramural Research (ZIC)
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National Cancer Institute Division of Basic Sciences
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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