Abstract 3286: A tissue engineered model of Ewing's sarcoma

Abstract

Abstract More than 90% of the deaths that occur in adolescents and young adults (AYA) suffering from Ewing sarcoma (ES), the second most common bone sarcoma, are a direct result of tumor metastasis from bone and growth within the lung. Yet, little is known about the bone or lung microenvironment and the critical role they play in promoting tumor survival, growth, and differentiation. Current preclinical models poorly reflect how ES behaves in patients and most rely upon 2D cell cultures that place tumor cells on flat plastic containers or within animals. Neither model adequately mimics human tumors and the resulting phenotypic drift from their human counterparts can lead to misleading preclinical results and drug candidates that seem promising in the lab but often disappoint when advanced to the clinic. In an attempt to overcome this notable challenge, our team of cancer biologists, bioengineers, and clinicians pioneered a tissue-engineered ex vivo bone tumor niche that better mimics the native behavior of malignant bone tumors. Briefly, this synthetic osseus niche - fabricated from biologically inert 10 μm electrospun PCL fibers - forms a minature wafer capable of fostering strong cell-matrix adhesion, in vivo-like expression of oncogenic protein targets, and a physiological cell proliferation rate that is better suited for evaluation of experimental cytotoxic drugs. Importantly, this tissue engineered preclinical ES model provides a unique opportunity to assess several of the most promising biologically targeted therapies, including those directed toward the pathognomonic EWS-FLI chromosomal translocation, mTOR, and IGF-1R (a critical drug target responsible for malignant transformation of ES from MSCs and oncogene addiction). Given the nascent convergence between the tissue engineering/regeneration and cancer biology fields, the advantages and potential pitfalls of tissue-engineered bone tumor models will be introduced and recent findings discussed, including identification of cell/ECM interactions that promote ES cell survival, maintain oncogenic proteomic signatures, and preserve an in-vivo like response to conventional and biologically targeted therapies. Unpublished work will be presented that highlights the ability of flow perfusion bioreactors to more uniformly distribute cells and nutrients throughout the ECM-saturated 3D scaffolds while increasing clearance of waste byproducts. In conclusion, a tissue engineered preclinical ES model allows scientists a unique opportunity to modulate and control key interactions between tumor cells, their adjacent microenvironment, and even heterotopic cells while simultaneously monitoring the impact of these interactions on cancer cell behavior. At the expense of reduced biological complexity, the more simplified ex vivo system is expected to shed new light on druggable targets tangent to the cells themselves, and in so doing, ultimately yield innovative therapies able to cure ES patients. Citation Format: Joseph A. Ludwig, Salah Lamhamedi Cherradi, Brian Menegaz, Marco Santoro, Antonios Mikos. A tissue engineered model of Ewing's sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3286. doi:10.1158/1538-7445.AM2015-3286