Abstract 283: Reconstructed plate-based 3D screening assays that predict in vivo responses

Abstract

Abstract In preclinical drug development, there is an urgency to create models that are predictive and relevant at the same time. To support this effort, early drug development emphasizes establishing multiple strategies that address treatment response, resistance, and combination effects, all with rapid turnover. Given the ever-increasing relevance of 3D in vitro models, Labcorp employs 3D model systems co-developed with zPREDICTA. These organ-specific models can support tumor cell growth and mimic the composition and architecture of both solid tumors and hematological malignancies. While 2D in vitro assays are preferred for screening efforts of chemical libraries, mainly because of cost, they do not recapitulate the tumor architecture and the microenvironment that is more comparable to in vivo models. This can result in differences in pharmacological potencies of standard of care (SoC) agents when compared to the 3D and in vivo models. zPREDICTA 3D assays serve as a tool for in vitro screening of tumor cell lines, which in long term cultures develop similar characteristics to in vivo disease states. Specifically, this in vitro system correlates well with breast and lung carcinoma in vivo models when matching rank order of potencies of known SoC agents. zPREDICTA tumor-specific 3D systems as well as 2D cultures and in vivo models were used to compare and contrast the activity of a set of anticancer agents. Human MDA-MB-231 cells were sensitive to paclitaxel both in 2D and in the 3D r-Breast (IC50 of 7.9nM and 6.1nM, respectively) as well as in vivo, with complete growth inhibition at the dose of 15mg/kg. Paclitaxel was cytotoxic in 2D cultures of murine 4T1 breast tumor cells (IC50=59nM), but not in the 3D reconstructed mouse breast model (r-mBreast) or in vivo, where the syngeneic 4T1 model was refractory to paclitaxel up to 10mg/kg. Similarly, NCI-H460 cells were sensitive to paclitaxel in 2D (IC50=2.3nM), while minimal response was seen in the 3D r-Lung model, and in vivo there was minimal response seen at a 20mg/kg treatment. These same cells were refractory to erlotinib in 2D, 3D, and in vivo. Additional SoC agents were profiled in these models and will also be discussed. Taken together these data demonstrate that zPREDICTA’s organ-specific 3D models mimic in vivo response with a higher fidelity than the standard 2D cultures. Additional in vitro reconstructed 3D histotype models are being developed and validated with the goal of providing faster and more predictive in vivo results. Citation Format: Sumithra Urs, Michael Steffey, Ying Qu, Matthew Ryou, Julia Kirshner, Scott Wise. Reconstructed plate-based 3D screening assays that predict in vivo responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 283.