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Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann-cell derived sarcomas. These tumors are resistant to all current therapies, with exception to gross total surgical resection, and unresectable or metastatic tumors are considered incurable. Our understanding of the molecular alterations driving malignant transformation is limited, and to date, targeted therapies have proven ineffective. In this study, we leverage multi-platform genomic and epigenomic profiling of human MPNSTs and neurofibromas to identify targetable molecular pathways that lead to malignant transformation. Unsupervised consensus hierarchical clustering of the top 20K most variable methylated probes yielded seven stable and robust subgroups that are clinically relevant. The high-grade MPNSTs formed two distinct methylation-based clusters (MPNST-G1 and MPNST-G2). MPNST-G1 had worse prognosis compared to MPNST-G2 (0.6 years versus 1.4 years, p &amp;lt; 0.05). PTCH1 loss or SMO gain was prevalent in MPNST-G1 compared to MPNST-G2 (75% vs 12.5%, p &amp;lt; 0.05). In addition, MPNST-G1 harbored PTCH1 CpG island promoter hypermethylation in (87.5% vs 12.5%, p &amp;lt; 0.001). Transcriptome profiling recapitulated the two distinct MPNST subgroups. We next demonstrated that that RB1 signaling pathways are aberrant in both MPNST-G1 and MPNST-G2. However, SHH pathway activation is observed in MPNST-G1, while WNT/CCND1/ ß-catenin pathway activation is observed in MPNST-G2. Network-based drug-disease proximity analysis identified SMO inhibitors as a potential FDA approved drug as a potential targeted therapy. To determine if SHH pathway activation is sufficient for malignant transformation, we knocked out PTCH1 in immortalized neurofibroma cells lines. In 3 different cell lines with PTCH1 knockout, we observed induction of a malignant phenotype, with increased cellular proliferation and invasion. Most importantly, in-vitro and in-vivo models confirm that targeting the SHH pathway, with sonidegib, was effective in inhibiting tumor growth proving SMO inhibition to be a novel therapeutic option in these lethal cancers.

EPCO-02. MOLECULAR CHARACTERIZATION OF TWO NOVEL MPNST SUBGROUPS IDENTIFIES THERAPEUTIC OPPORTUNITIES