TY - JOUR
T1 - Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology
AU - Larsson, Alex T.
AU - Bhatia, Himanshi
AU - Calizo, Ana
AU - Pollard, Kai
AU - Zhang, Xiaochun
AU - Conniff, Eric
AU - Tibbitts, Justin F.
AU - Rono, Elizabeth
AU - Cummins, Katherine
AU - Osum, Sara H.
AU - Williams, Kyle B.
AU - Crampton, Alexandra L.
AU - Jubenville, Tyler
AU - Schefer, Daniel
AU - Yang, Kuangying
AU - Lyu, Yang
AU - Pino, James C.
AU - Bade, Jessica
AU - Gross, John M.
AU - Lisok, Alla
AU - Dehner, Carina A.
AU - Chrisinger, John S.A.
AU - He, Kevin
AU - Gosline, Sara J.C.
AU - Pratilas, Christine A.
AU - Largaespada, David A.
AU - Wood, David K.
AU - Hirbe, Angela C.
N1 - Publisher Copyright:
© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
PY - 2023/11/1
Y1 - 2023/11/1
N2 - 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 (<50%). We evaluated drug response to “robust” or “good” microtissues, namely MN-2, JH-2-002, 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. 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.
AB - 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 (<50%). We evaluated drug response to “robust” or “good” microtissues, namely MN-2, JH-2-002, 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. 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.
KW - 3D microtissues
KW - NF1-MPNST
KW - PDX
KW - drug screening
KW - genomic variants
UR - http://www.scopus.com/inward/record.url?scp=85174542218&partnerID=8YFLogxK
U2 - 10.1093/neuonc/noad097
DO - 10.1093/neuonc/noad097
M3 - Article
C2 - 37246765
AN - SCOPUS:85174542218
SN - 1522-8517
VL - 25
SP - 2044
EP - 2057
JO - Neuro-oncology
JF - Neuro-oncology
IS - 11
ER -