Novel Therapeutic Development of NF1-Associated Malignant Peripheral Nerve Sheath Tumor (MPNST)
Abstract
NF1-assocaited MPNST accounts for ~50% of all MPNSTs and is one of the most difficult subtypes of soft tissue sarcoma to manage, given its poor sensitivity to conventional systemic therapy and radiotherapy and high likelihood to metastasize. Novel therapeutic development is imperative. Using comprehensive and integrative genomic approaches, we have identified recurrent inactivating genetic alterations of three central pathways: PRC2 (80%) core components (EED or SUZ12), CDKN2A (81%) and NF1 (72% of non-NF1-associated) in all MPNSTs, and the three components significantly co-occur, suggesting their critical and cooperative roles in MPNST pathogenesis. We demonstrated that MPNSTs with complete PRC2 loss showed complete loss of H3K27me3 and aberrant transcriptional activation of multiple PRC2-transcriptional targets. Here, we have further validated the high sensitivity and specificity of using H3K27me3 as a diagnostic biomarker for high-grade MPNST. The evaluation of using H3K27me3 as a prognostic biomarker in MPNST is ongoing. Therapeutically, we have found that the combination of MEK inhibitor and CDK4 inhibitor resulted in at least additive effects of growth suppression of human MPNST cell lines in vitro; We are currently evaluating newer generations of epigenetic therapeutics in PRC2-loss MPNST cells. These studies will be extended to in vivo xenograft studies and relevant genetically engineered MPNST mouse models.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2016
- Accession Number
- AD1019302
Entities
People
- Ping Chi