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Since Ewing sarcoma (ES) is a stem cell-like cancer1, improved outcome for some patients will be realised when treatments to eradicate ES stem-like cells (ES-CSCs) are evaluated in clinical trials. Therefore, we have identified small molecules that kill ES-CSCs, and examined their efficacy alone and in combination with chemotherapy. ES patient-derived cultures and paired ES-CSCs established from treatment-naïve tumors were investigated1. The effect of 1293 small molecules (5µM, 48h) on ES-CSC cell number was examined using high content imaging (Operetta). The effect of the most active small molecules was examined in combination with chemotherapies used to treat ES using high content imaging and CalcuSyn (Biosoft). ES-CSCs were more resistant to chemotherapy than paired patient derived cells (p We have identified small molecules that kill patient-derived ES-CSCs and confirmed they have synergistic activity with classic chemotherapies, supporting our hypothesis that ES-CSC targeted drugs in combination with existing chemotherapies is a promising therapeutic strategy. 1 Roundhill et al. 2021. Cellular Oncology, 44(5):1065-1085 Table 1. Summary of synergy between the aurora kinase inhibitors and chemotherapeutic agents in 4 patient-derived cell cultures (ES1 - ES4). Patient derived cells were treated with increasing concentrations of chemotherapies and small molecules (0.25x, 0.5x, 2x, 4x the EC50). Concentration range of doxorubicin=0.08-6.7µM, vincristine=0.01-1.5µM, etoposide=0.01-33µM, actinomycin-D=0.02-10µM, carboplatin=8.4-135µM, 4-hyperoxyifosfamide=2.6-152µM, CCT137690=0.07-14µM, CD532=0.05-14µM. Where data is available, concentrations did not exceed the maximum achievable concentration in plasma (Liston and Davis. 2017. Clinical Cancer Research, 15(14):3489-3498). Synergy = combination index Citation Format: Elizabeth A. Roundhill, Lee Jeys, Michael Parry, Kenneth S. Rankin, Richard Foster, Jacquelyn Bond, Susan Burchill. Enhancing the efficacy of conventional chemotherapy with novel targeted small molecules to kill Ewing sarcoma cancer stem-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1847. |
