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-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.

CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon restoration of RB function in malignant peripheral nerve sheath tumors

“…SHP099 also demonstrated activity against cellular viability in a 3D microtissue ex-vivo model derived from four unique MPNST PDX [Fig S2A, ref. ( 9 )]. Further investigation in ST8814 and JH-2-079c cell lines ( 9 ) treated with DMSO or 0.3 μmol/L TNO155, using Incucyte real-time monitoring system, demonstrated caspase-3/7 activation induced by TNO155 (Fig S2B).…”

“…( 9 )]. Further investigation in ST8814 and JH-2-079c cell lines ( 9 ) treated with DMSO or 0.3 μmol/L TNO155, using Incucyte real-time monitoring system, demonstrated caspase-3/7 activation induced by TNO155 (Fig S2B). Mechanistically, we found that TNO155 inhibited SHP2 phosphatase activity as evidenced by p-SHP2 reduction, and markedly suppressed ERK signaling and downstream cell cycle pathways, in a dose-dependent (Fig 2D) and time-dependent (Fig 2E) manner.…”

“…3D microtissue assay was described previously ( 9 ). All mouse experiments were approved by the IACUC at University of Minnesota under protocol #2101-38758A.…”

“…(4)(5)(6)(7)], and TP53, as well as gain of chromosome 8 [80%, ref. (8,9)] yet, molecular targeting of these LOF alterations represents a unique challenge and a major unmet need for these patients.…”