Abstract 4935: Development of a human pancreatic tumor microenvironment system (TMeS) for evaluation of novel therapeutics

The development of drugs to treat cancer is severely hampered by the inefficiency of translating pre-clinical in vitro and mouse studies into clinical benefit. Over 90% of drugs that progress through pre-clinical studies fail in human trials. Therefore, there is a critical need to improve the accuracy of evaluating pre-clinical drug efficacy through the development of more physiologically relevant human models. This is especially the case for pancreatic cancer, the 4th leading cause of cancer deaths with a 5-year survival rate of <6%, where new therapies are desperately needed. The tumor microenvironment (TME) of PDAC contains numerous cell types including vascular endothelial cells, stellate cells and fibroblasts, as well as a complex extracellular matrix (ECM), all of which contribute to the growth and survival of cancer cells, as well as posing potential targets for therapeutic intervention. Thus, a more complete and nuanced understanding of the PDAC TME is required for the rational development of effective therapies. To address this problem, an in vitro tumor microenvironment system (TMeS) was engineered to incorporate tumor capillary hemodynamics and biological transport with co-cultured human microvascular endothelial cells, along with pancreatic tumor and stellate cells. We demonstrate that significant tumor cell transcriptomic changes occur in the TMeS that correlate with the in vivo xenograft transcriptome, including alterations in cell cycle regulation, oncogene signaling, and metabolism. PDAC tumor cells from two patients were inhibited by the human Cmax dose of gemcitabine to levels paralleling the patients’ clinical responses. Previous work demonstrated that the FAK inhibitor, PF-562,271, worked only on in vivo xenografts and not on 2D in vitro PDAC cultures and here we show that PF-562,271 effectively inhibited PDAC growth in the TMeS indicating in vivo-like drug responses. In sum, the TMeS recapitulates the in vivo xenograft transcriptional program and responds to both established and experimental small molecule inhibitor chemotherapeutics at concentrations that correspond to human therapeutic plasma levels. Therefore, this model provides a unique platform to rigorously test the contributions of the cellular and molecular components of the TME through manipulating individual constituents in a controlled fashion that is not possible in vivo. Moreover, the TMeS can be used for the rapid evaluation of novel precision therapies. Finally, this system is amenable to using patient tumor material directly, enabling the potential use of the TMeS for patient avatars. Citation Format: Daniel G. Gioeli, Chelsi Snow, Michael Simmers, Robert Figler, J. Thomase Parsons, Stephen Hoang, Todd Bauer, Brian Wamhoff. Development of a human pancreatic tumor microenvironment system (TMeS) for evaluation of novel therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4935. doi:10.1158/1538-7445.AM2017-4935