Abstract LB-325: New synergistic mTOR-based combinations for the treatment of Ewing sarcoma

Abstract Ewing sarcoma (ES), an aggressive bone cancer in children and young adults, is dependent upon the insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) cell-signaling axis for malignancy, survival, and metastasis. Individual targeting of mTOR has negligible anti-tumor activity in ES, and single-agent IGF-1R targeting leads to only transient effects that benefit only 10-14% of patients. Co-targeting strategies using IGF-1R Abs combined with mTOR inhibitors were shown in 2012 to increase response rates to 29% but the high toxicity profile limited subsequent clinical development. While an ongoing COG protocol combines IGF-1R Abs with standard-of-care cytotoxic chemotherapy in newly diagnosed ES patients harboring metastatic disease, this combination is unlikely to benefit those who have recurred or developed chemoresistant disease. Herein, we present several highly synergistic drug combinations using novel biologically-targeted therapies aimed at the IGF-1R/mTOR pathway. A dual-specific anti-IGF-1/IGF-2 human monoclonal antibody (m708.5), which binds human IGF-1 and IGF-2 with high pico-molar affinity, potently inhibited phosphorylation of the IGF-1R and the insulin receptor (IR) in an EW5 xenograft animal model of ES. In concert with mTOR inhibitors (e.g., everolimus or ridaforolimus), m708.5 demonstrated striking tumor regression and prolonged mouse survival. Additionally, we expand upon the synergistic role of CRM1 (XPO1) in combating ES tumor growth. A small molecule inhibitor of this protein (KPT-330) was previously shown to attenuate IGF-1-induced activation of IGF-1R when combined with a small-molecule inhibitor of IGF-1R and IR (Linsitinib, OSI906). Our results indicate superior preclinical anti-tumor activity when it is combined with everolimus in our xenograft ES models. Though these combinations have not yet been assessed in the clinical setting, early-phase clinical trials have begun testing KPT-330 in select sarcoma subtypes, and a host of mTOR inhibitors are FDA-approved and widely available. Our data supports several novel drug combinations that could rapidly be explored in the clinic to improve survival of ES patients. SELC & JAL: Co-senior Authors Citation Format: Brian A. Menegaz, Branko Cuglievan, Prasad S. Admane, Feng Yang, Dimitrov Dimiter, Yosef Landesman, Salah-Eddine Lamhamedi Cherradi, Joseph A. Ludwig. New synergistic mTOR-based combinations for the treatment of Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-325.