Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology

Autor: Alex T Larsson, Himanshi Bhatia, Ana Calizo, Kai Pollard, Xiaochun Zhang, Eric Conniff, Justin F Tibbitts, Elizabeth Rono, Katherine Cummins, Sara H Osum, Kyle B Williams, Alexandra L Crampton, Tyler Jubenville, Daniel Schefer, Kuangying Yang, Yang Lyu, James C Pino, Jessica Bade, John M Gross, Alla Lisok, Carina A Dehner, John S A Chrisinger, Kevin He, Sara J C Gosline, Christine A Pratilas, David A Largaespada, David K Wood, Angela C Hirbe
Rok vydání: 2023
Předmět:
Zdroj: Neuro-Oncology.
ISSN: 1523-5866
1522-8517
DOI: 10.1093/neuonc/noad097
Popis: Background Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that often develop in patients with neurofibromatosis type 1 (NF1). To address the critical need for novel therapeutics in MPNST, we aimed to establish an ex vivo 3D platform that accurately captured the genomic diversity of MPNST and could be utilized in a medium-throughput manner for drug screening studies to be validated in vivo using patient-derived xenografts (PDX). Methods Genomic analysis was performed on all PDX-tumor pairs. Select PDX were harvested for assembly into 3D microtissues. Based on prior work in our labs, we evaluated drugs (trabectedin, olaparib, and mirdametinib) ex vivo and in vivo. For 3D microtissue studies, cell viability was the endpoint as assessed by Zeiss Axio Observer. For PDX drug studies, tumor volume was measured twice weekly. Bulk RNA sequencing was performed to identify pathways enriched in cells. Results We developed 13 NF1-associated MPNST-PDX and identified mutations or structural abnormalities in NF1 (100%), SUZ12 (85%), EED (15%), TP53 (15%), CDKN2A (85%) and chromosome 8 gain (77%). We successfully assembled PDX into 3D microtissues, categorized as robust (>90% viability at 48h), good (>50%), or unusable ( Conclusions These data support the successful establishment of a novel 3D platform for drug discovery and MPNST biology exploration in a system representative of the human condition.
Databáze: OpenAIRE
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