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

Abstract

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). 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. 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 (<50%). We evaluated drug response to “robust” or “good” microtissues, namely MN-2, JH-2-002,more » JH-2-079-c, and WU-225. Drug response ex vivo predicted drug response in vivo, and enhanced drug effects were observed in select models. 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.« less

Authors:

Larsson, Alex T.  ^[1];

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• Search DOE PAGES for ORCID "0000-0002-1350-8271"

Bhatia, Himanshi ^[2]; Calizo, Ana ^[3]; Pollard, Kai ^[3]; Zhang, Xiaochun ^[2]; Conniff, Eric ^[1]; Tibbitts, Justin F. ^[1]; Rono, Elizabeth ^[1]; Cummins, Katherine ^[1]; Osum, Sara H. ^[1]; Williams, Kyle B. ^[1]; Crampton, Alexandra L. ^[1]; Jubenville, Tyler ^[1]; Schefer, Daniel ^[2]; Yang, Kuangying ^[2]; Lyu, Yang ^[2]; Pino, James C. ^[4]; Bade, Jessica  ^[4];

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• Search DOE PAGES for ORCID "0000-0001-7595-0017"

Gross, John M. ^[5]; Lisok, Alla ^[3] more »; Dehner, Carina A. ^[2]; Chrisinger, John S. A. ^[2]; He, Kevin ^[2]; Gosline, Sara J. C. ^[4]; Pratilas, Christine A. ^[3]; Largaespada, David A. ^[1]; Wood, David K. ^[1]; Hirbe, Angela C.  ^[2]

• Search DOE PAGES for author "Hirbe, Angela C."
• Search DOE PAGES for ORCID "0000-0003-1719-0771"

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+ Show Author Affiliations

1. Univ. of Minnesota, Minneapolis, MN (United States)
2. Washington Univ., St. Louis, MO (United States)
3. Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine
4. Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
5. Johns Hopkins Univ., Baltimore, MD (United States)

Publication Date:

Mon May 29 00:00:00 EDT 2023

Research Org.:

Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Org.:

USDOE

OSTI Identifier:

2305670

Report Number(s):

PNNL-ACT-SA-10646
Journal ID: ISSN 1522-8517

Grant/Contract Number:  

AC05-76RL01830

Resource Type:

Accepted Manuscript

Journal Name:

Neuro-Oncology

Additional Journal Information:

Journal Volume: 25; Journal Issue: 11; Journal ID: ISSN 1522-8517

Publisher:

Oxford University Press

Country of Publication:

United States

Language:

English

Subject:

60 APPLIED LIFE SCIENCES; drug therapy; genomic variants; MPNST; microtissues; PDX; drug screening, NF1; drug response; genome; nerve sheath tumors; neoplasms; olaparib; trabectedin