1. IGF1R targeted agents: Working with Dr. Lee Helman, we 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. We also have 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 (Mayeenuddin et al., Oncogene 29:6367-6377, 2010). Working with Dr. Raffit Hassan, it was found that IGF1R antibody was active in mesothelioma is correlated with IGF-IR sites/cell (Kalra et al., Int J Cancer 131:2143-52, 2012). Collaborating with Dr. Lee Helman, our recent data showed that elevated IFG1R was associated with worse prognosis of rhabdomyosarcoma the resistance to IGF1R targeted antibody was associated with the down regulation of IGFBP2 in rhabdomyosarcoma (Kang et al., Oncogene, 33:5697-705, 2014). 2. Death Receptor targeted agents To identify novel agents with selective activity against sarcoma and biomarkers predictive of responses, we investigated a death receptor targeted antibodies in pediatric cancers. In working with Genentech, We showed 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. We observed that the caspase-8 expression is predictive to the response to drozitumab. More importantly, caspase-8 catalytic activity was both necessary and sufficient for mediating the sensitivity to drozitumab. We results further showed Drozitumab was effective in vitro and in vivo, and may provide long-term control of RMS (Kang Clin. Cancer Res. 2011). Our recent study has been focused on an M-CRADA with Amgen to evaluate their therapeutic antibody conatumumab against Ewing's sarcoma. Our preclinical study indicates their sensitivity to human DR5 agonist antibody conatumumab in vitro, which induces rapid activation of caspase-8 and apoptosis. Further analysis reveals the correlation of sensitivity to conatumumab with the expression of caspase-8, with its catalytic activity both necessary and sufficient to confer such sensitivity. In vivo, conatumumab is active against both a EWS cell line and a patient-derived xenograft with higher caspase-8 expression, but is not effective against another patient-derived xenograft with lower caspase-8 expression. These studies suggest the potential of conatumumab as a therapeutic agent against Ewing's sarcoma and caspase-8 expression may serve as a predictive biomarker (Kang et al, Brit J of Cancer 2015). 3. SLFN11 as a biomarker for drug response in Ewing's sarcoma. In working with Dr. Yves Pommier, we showed that SLFN11 is a direct target of EWS-FLI1 oncogene and contributes to drug response of top-1 inhibitors in Ewing's sarcoma (Tang et al., Clin Cancer Res. 2015).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Scientific Cores Intramural Research (ZIC)
Project #
1ZICBC011048-09
Application #
9344164
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2016
Total Cost
Indirect Cost
Name
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