Abstract
Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that often develop in patients with neurofibromatosis type 1 (NF1-MPNST), but can occur sporadically. Through a multi-institution collaboration, we have developed 13 NF1-associated MPNST patient-derived xenografts (PDX). Genomic analysis of the PDX-tumor pairs identified somatic mutations in NF1 (61%), SUZ12 (61%), EED (15%), and TP53 (15%), and chromosome 8 (Chr8) gain (77%), consistent with published data. Pre-clinical models that capture this molecular heterogeneity are needed to identify and prioritize effective drug candidates for clinical translation. Here, we describe the successful development of a medium-throughput ex vivo 3D microtissue model with several advantages over 2D cell line growth, which can be utilized to predict drug response in vivo. Herein, we present proof-of-principle of this PDX-to-microtissue system, using four genomically representative MPNST and three drugs. This work highlights the development of a novel ex vivo to in vivo preclinical platform in MPNST that successfully captures the genomic diversity observed in patients and represents a resource to identify future therapeutic strategies.
Competing Interest Statement
Dr. Angela C. Hirbe has served as a consultant for SpringWorks Therapeutics and AstraZeneca. She also receives grant funding from Tango Therapeutics. Dr. David A. Largaespada is a co-founder of and has equity in NeoClone Biotechnology, Inc., Immusoft, Inc., and Luminary Therapeutics, Inc. and is a Senior Scientific Advisor and on the Board of Directors of Recombinetics, Inc. Some of his research is funded by Genentech, Inc. Dr. Christine A. Pratilas has received consulting fees from Genentech/Roche and Day One Therapeutics; and receives research grant funding from Kura Oncology and Novartis Institute for Biomedical Research.
Footnotes
This version of the manuscript has been revised to update the Acknowledgements section with additional funding details - Research reported in this publication was partially supported by the National Cancer Institute of the National Institutes of Health under Award Number U54CA224083. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
