Preclinical Development of Novel Targeted Therapeutics Against Pediatric Sarcoma

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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. A manuscript on this study has been accepted for publication. 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).