Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology
Bhatia^, H.; Larsson^, A. T.; Calizo^, A.; Pollard, K.; Zhang, X.; Conniff, E.; Tibbitts, J. F.; Osum, S. H.; Williams, K. B.; Crampton, A. L.; Jubenville, T.; Schefer, D.; Yang, K.; Lyu, Y.; Bade, J.; Pino, J. C.; Gosline, S. J.; Pratilas, C. A.; Largaespada, D. A.; Wood, D. K.; Hirbe, A. C.
Show 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.
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