Abstract 5720: Combination therapies in matched 3D in vitro and in vivo preclinical models of rare and recalcitrant cancers from the National Cancer Institute’s Patient-Derived Models Repository
Authors: Dexheimer Thomas S. , Silvers Thomas , Delosh Rene , Reinhart Russell , Ogle Chad , Davoudi Zahra , Jones Eric , Trail Debbie , Carter John , Mills Justine , Georgius Kyle , Stotler Howard , Norris Michelle , Uzelac Shannon , Borgel Suzanne , Minor Tiffanie , Stockwin Luke , Mullendore Michael , Plater Kevin , Kalmbach Keegan , Steed Jessica , Murphy Matthew , Bliss Gareth , Bonomi Carrie , Dougherty Kelly , Gibson Marion , Cooper Kevin , Newton Dianne , Timme Cindy R. , Evrard Yvonne A. , Hollingshead Melinda G. , Coussens Nathan P. , Parchment Ralph E. , Doroshow James H. , Teicher Beverly A. 
Published: April 2023

Abstract
There is a major need in oncology drug development to establish predictive preclinical assays with high translational relevance to patient responses. The National Cancer Institute’s Patient-Derived Models Repository (https://pdmr.cancer.gov) offers a collection of highly characterized models from a variety of cancer types including rare and recalcitrant malignancies and tumors from patients of diverse ancestry. This collection includes matched sets of patient-derived cell lines, organoids, and xenografts (PDXs), which allows comparisons of drug responses from in vitro and in vivo assays performed with the same patient-derived tumor model. A high-throughput screen was conducted using matched sets of patient-derived organoids and cell lines. Patient-derived cell lines were grown as 3D multicellular spheroids mixed with endothelial cells and mesenchymal stem cells. The patient-derived organoids were 100% tumor cells and were plated in 5% basement membrane extract supplemented with growth factors and cytokines. All drugs were tested at concentrations up to their reported clinical Cmax values and cell viability for individual drug treatments and drug combinations were assayed using CellTiter-Glo 3D after seven days drug exposure. Prior to the endpoint viability measurements, growth curves for spheroid median volume and organoid median surface area were calculated from a series of non-invasive brightfield images collected every 12 hours. For some drug combinations, differential responses were observed between the matched organoids and multicellular spheroids, potentially reflecting the contribution of the stromal component in the spheroids. Overall, the drug-dependent growth responses observed from the two 3D in vitro models (i.e., multicellular spheroids and organoids) were frequently comparable to those observed in vivo from PDXs. For example, the in vitro activities of several drug combinations including: BAY1895344 + temozolomide, erlotinib + cediranib, entinostat + talazoparib, and selumetinib + abemaciclib, demonstrated good agreement with the responses observed in vivo. However, among the drug combinations tested ixazomib + panobinostat showed the greatest cytotoxicity in vitro but had no activity in the matched PDX models. The availability of matched patent-derived cell lines, organoids and PDXs provides an opportunity to learn about the features of assay methodologies and data analyses that influence the successful translation of preclinical results between in vitro and in vivo systems. The results of this study are encouraging, but also highlight discrepancies that will be important to investigate, understand and address in order to improve translational capacity of future assays. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I.
Citation Format: Thomas S. Dexheimer, Thomas Silvers, Rene Delosh, Russell Reinhart, Chad Ogle, Zahra Davoudi, Eric Jones, Debbie Trail, John Carter, Justine Mills, Kyle Georgius, Howard Stotler, Michelle Norris, Shannon Uzelac, Suzanne Borgel, Tiffanie Minor, Luke Stockwin, Michael Mullendore, Kevin Plater, Keegan Kalmbach, Jessica Steed, Matthew Murphy, Gareth Bliss, Carrie Bonomi, Kelly Dougherty, Marion Gibson, Kevin Cooper, Dianne Newton, Cindy R. Timme, Yvonne A. Evrard, Melinda G. Hollingshead, Nathan P. Coussens, Ralph E. Parchment, James H. Doroshow, Beverly A. Teicher. Combination therapies in matched 3D in vitro and in vivo preclinical models of rare and recalcitrant cancers from the National Cancer Institute’s Patient-Derived Models Repository. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5720.