Building liquid-liquid perfusion interface (LLPI) –based patient-derived tumoroids (PDTs) model system as clinical research tools for testing cancer therapeutics.

Abstract

e15192 Background: Current in vitro cancer model systems are inadequate in their representation and application of an actual tumor. Use of three-dimensional PDTs that consists of stroma and the microenvironment vastly addresses these shortcomings. However, a complete picture of the intratumoral interactions and functions requires optimal supply of oxygen to address problems associated with poor cellular oxygenation. Soft tissue sarcomas are malignant tumors that develop in the tissues that surround and support bones and organs. For non-resectable soft tissue sarcomas, model systems and treatment options are either limited or not available. We are establishing our Matrigel-based PDTs on a Liquid-Liquid Perfusion Interface (LLPI) using a synthetic hemoglobin as a blood substitute to build a comprehensive model system that is an amalgamation of an in vitro-in vivo system. Our objective is to replicate tumor complexity and use our model to serve as an effective and reliable platform to test and investigate therapeutic options. Methods: Soft tissue sarcoma PDT models with LLPI were built and used for testing under the following groups: Drug treatments with Doxorubicin (10nM), HSP90 inhibitor (1)10 nM, (2) 100 nM and (3) 1 mM) and combination (Doxorubicin + HSP90) for 10 days was compared on Sarcoma PDT models with and without oxygenation to test the impact of oxygen on tumor volume. Currently we are pursuing downstream analysis using apoptosis, proliferation and cytokine profiling and dynamic oxygen analysis of the TME. Results: We compared the effect of Doxorubicin with HSP90 inhibitor on a Sarcoma PDT model with and without oxygenation to observe the impact of oxygen on tumor growth. We observed similar rate of cell growth in the untreated samples in both model systems. In the non-oxygenated PDTs Doxorubicin-HSP90 combination was effective in reducing tumor volume. In the oxygenated PDTs the efficacy of the combination therapy (Doxorubicin+HSP90) was no longer observed. Conclusions: The oxygenation status impacts the effect of Doxorubicin, HSP90 combination, a critical influence that would not have been observable without the use of oxygenated PDT model system. The impact of intratumoral variations on oxygenation levels warrants testing other existing and novel therapeutics on oxygenated PDT model systems to investigate the extent of the influence of oxygenation on the tumor biology. [Table: see text]