Abstract 6768: Matched XPDX™derivative models as a platform for continuity across preclinical drug development

Abstract

Abstract Drug discovery is a reductive process in which druglike entities are carried through increasingly complex assay formats to tease out the compounds best suited for human studies. In vivo efficacy remains the benchmark for successful preclinical drug development. Cell-based models are a mainstay in early stages but translatability of different models across platforms remains a challenge. In oncology, patient-derived xenografts (PDX) are the gold standard for animal studies because they recapitulate key features of human tumors including the cellular heterogeneity, growth patterns, and drug response of the original patient tumor. Ex vivo, PDX derivatives have the potential to harness these same traits thereby extending the utility of PDX models to earlier stages of preclinical drug development. The KIYA-Predict™ platform is a clinically validated tool for the assessment of ex vivo drug responses across a broad range of drug classes that when applied to XPDX models shows good correlation to in vivo drug responses and excellent intra-sample reproducibility over time. Working with the well-characterized XenoSTART™ XPDX model repository, Kiyatec has derived 2D cell lines and organotypic 3D-expansion cultures to complement the ex vivo predictive value of our KIYA-PREDICT™ XPDX drug response profiling (DRP) platform. The development of syngeneic models applicable to simpler, high-throughput library screening (2D formats) and lower-throughput more complex mechanistic studies (3D organotypic models) could alleviate the burden and pitfalls of extrapolating data across unrelated models. Matched sets of 2D cell lines (2D-XPDX™) and 3D organotypic (XPDXO™) cultures were established from single cell suspensions of digested, mouse-cell depleted XPDX™ tissue samples. Drug response profiling of the XPDX™ in their various ex vivo culture formats showed relative similarities across platforms. Genomic profiling of the derivates confirmed shared tissue origin and retention of genomic and phenotypic signatures to varying degrees across models. Mechanistic evaluation of 3D organotypic culture demonstrated that disease-relevant biomarkers and processes are maintained. Together these results demonstrate the feasibility of this novel drug discovery platform that avoids ambiguity imparted by discordant models. Citation Format: Melissa Millard, Aaron Carlson, Danielle Y. Nadeau, Kimberly J. Burgess, Alyssa Simonson, Armando Diaz, Michael Wick, Teresa DesRochers. Matched XPDX™derivative models as a platform for continuity across preclinical drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6768.