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We present preliminary results that quantify network robustness and fragilityof Ewing sarcoma (ES), a rare pediatric bone cancer that often exhibits de novoor acquired drug resistance. By identifying novel proteins or pathwayssusceptible to drug targeting, this formalized approach promises to improvepreclinical drug development and may lead to better treatment outcomes. Towardthat end, our network modeling focused upon the IGF-1R-PI3K-Akt-mTOR pathway,which is of proven importance in ES. The clinical response and proteomicnetworks of drug-sensitive parental cell lines and their drug-resistantcounterparts were assessed using two small molecule inhibitors for IGF-1R(OSI-906 and NVP-ADW-742) and an mTOR inhibitor (mTORi), MK8669, such thatprotein-to-protein expression networks could be generated for each group. Forthe first time, mathematical modeling proves that drug resistant ES samplesexhibit higher degrees of overall network robustness (e.g., the ability of asystem to withstand random perturbations to its network configuration) to thatof their untreated or short-term (72-hour) treated samples. This was done byleveraging previous work, which suggests that Ricci curvature, a key geometricfeature of a given network, is positively correlated to increased networkrobustness. More importantly, given that Ricci curvature is a local property ofthe system, it is capable of resolving pathway fragility. In this note, weoffer some encouraging yet limited insights in terms of system-level robustnessof ES and lay the foundation for scope of future work in which a complete studywill be conducted.

An Analytical Approach for Insulin-like Growth Factor Receptor 1 and Mammalian Target of Rapamycin Blockades in Ewing Sarcoma