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Combinatorial Drug Screening Identifies Ewing Sarcoma-specific Sensitivities
Branka Radic-Sarikas1, Kalliopi P Tsafou2,3, Kristina B Emdal4
1CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Abstract:
Improvements in survival for Ewing sarcoma pediatric and adolescent patients have been modest over the past 20 years. Combinations of anticancer agents endure as an option to overcome resistance to single treatments caused by compensatory pathways. Moreover, combinations are thought to lessen any associated adverse side effects through reduced dosing, which is particularly important in childhood tumors. Using a parallel phenotypic combinatorial screening approach of cells derived from three pediatric tumor types, we identified Ewing sarcoma-specific interactions of a diverse set of targeted agents including approved drugs. We were able to retrieve highly synergistic drug combinations specific for Ewing sarcoma and identified signaling processes important for Ewing sarcoma cell proliferation determined by EWS-FLI1 We generated a molecular target profile of PKC412, a multikinase inhibitor with strong synergistic propensity in Ewing sarcoma, revealing its targets in critical Ewing sarcoma signaling routes. Using a multilevel experimental approach including quantitative phosphoproteomics, we analyzed the molecular rationale behind the disease-specific synergistic effect of simultaneous application of PKC412 and IGF1R inhibitors. The mechanism of the drug synergy between these inhibitors is different from the sum of the mechanisms of the single agents. The combination effectively inhibited pathway crosstalk and averted feedback loop repression, in EWS-FLI1-dependent manner. Mol Cancer Ther; 16(1); 88-101. ©2016 AACR.
Insights
New drug combinations show promise for treating Ewing sarcoma, a rare pediatric cancer. Researchers identified synergistic drug pairings that target specific cancer cell pathways, potentially improving survival rates for young patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Survival rates for pediatric and adolescent Ewing sarcoma patients have seen limited improvement over two decades.
- Anticancer drug combinations are explored to overcome treatment resistance and reduce adverse effects via lower doses, crucial for childhood cancers.
Purpose of the Study:
- To identify Ewing sarcoma-specific synergistic drug combinations using a phenotypic screening approach.
- To elucidate the molecular mechanisms underlying the synergistic effects of targeted agents in Ewing sarcoma.
Main Methods:
- Utilized a parallel phenotypic combinatorial screening of cells from three pediatric tumor types.
- Generated a molecular target profile of PKC412 and analyzed synergistic effects with IGF1R inhibitors using quantitative phosphoproteomics.
Main Results:
- Identified highly synergistic drug combinations specifically for Ewing sarcoma, targeting EWS-FLI1-dependent signaling pathways.
- Uncovered a novel synergistic mechanism between PKC412 and IGF1R inhibitors that inhibits pathway crosstalk and feedback loops.
Conclusions:
- Synergistic drug combinations, particularly PKC412 and IGF1R inhibitors, offer a promising strategy for Ewing sarcoma treatment.
- The identified molecular mechanisms provide a basis for developing more effective targeted therapies for this pediatric cancer.
