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

Abstract 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 capt...

Full description

Saved in:
Bibliographic Details
Published in:Neuro-oncology (Charlottesville, Va.) Va.), 2023-11, Vol.25 (11), p.2044-2057
Main Authors: Larsson, Alex T, Bhatia, Himanshi, Calizo, Ana, Pollard, Kai, Zhang, Xiaochun, Conniff, Eric, Tibbitts, Justin F, Rono, Elizabeth, Cummins, Katherine, Osum, Sara H, Williams, Kyle B, Crampton, Alexandra L, Jubenville, Tyler, Schefer, Daniel, Yang, Kuangying, Lyu, Yang, Pino, James C, Bade, Jessica, Gross, John M, Lisok, Alla, Dehner, Carina A, Chrisinger, John S A, He, Kevin, Gosline, Sara J C, Pratilas, Christine A, Largaespada, David A, Wood, David K, Hirbe, Angela C
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Basic and Translational Investigations
drug response
drug screening, NF1
drug therapy
genome
genomic variants
Humans
microtissues
MPNST
Mutation
neoplasms
Nerve Sheath Neoplasms - pathology
nerve sheath tumors
Neurofibromatosis 1 - pathology
Neurofibrosarcoma - pathology
olaparib
PDX
Precision Medicine
trabectedin
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract 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. Selected 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 48 h), good (>50%), or unusable (
ISSN:1522-8517
1523-5866
DOI:10.1093/neuonc/noad097