Novel Therapeutic Development of NF1-Associated Malignant Peripheral Nerve Sheath Tumor (MPNST)
Abstract
Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder that affects approximately 1 in 3000 people. Although multiple defects can arise, malignant peripheral nerve sheath tumor (MPNST) represents the most common and deadly malignant tumors, leading to significant morbidity and mortality in NF1 patients. Clinically, NF1-assocaited MPNST accounts for ~50% of all MPNSTs and is one of the most difficult subtypes of soft tissue sarcomas 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 recently identified recurrent loss of function 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. These data suggest that, despite the clinical and histological heterogeneity, the NF1-associated, sporadic and RT-associated MPNSTs represent a relatively homogeneous group of disease at the molecular level. We also demonstrated that MPNSTs with complete PRC2 loss showed complete loss of H3K27me3 and aberrant transcriptional activation of multiple PRC2-repressed homeobox master regulators and their regulated developmental pathways. Introduction of the PRC2 component in a PRC2-deficient MPNST cell line restored H3K27me3 and decreased cell growth. The highly recurrent and specific inactivation of PRC2, NF1, and CDKN2A posits their critical and potentially cooperative roles in MPNST pathogenesis. These observations point to two central questions that will be the focus of the proposal here: (1) Does the H3K27me3 immunostaining correlate with clinical outcome? (2) Can we target the CDKN2A loss, NF1 loss, PRC2 loss? In this study, we propose to systematically evaluate the potential of H3K27me3 immunostaining as a prognostic biomarker by correlating the H3K27me3 IHC status with overall survival and disease related survival. Moreover, based on the oncogenomics discovery, we rationalize that the combined inhibition of the CDK4/6-RB pathway and the MAP kinase pathway might be an effective therapeutic strategy in CDKN2A and NF1 loss MPNSTs. In addition, to target PRC2-loss MPNSTs, we have identified a p300/CBP small molecule inhibitor that has selective inhibitory effects of the PRC2-loss MPNST compared to the PRC2-wt MPNST cells. We will further evaluate these two therapeutic strategies in in vivo MPNST models. Since both therapeutic strategies entail the use of compounds that are currently in clinical development, if they are proven effective in our in vivo studies, we can rapidly translate these therapeutic strategies into early phase clinical trials that may direct impact patients with MPNSTs, including NF1-associated MPNSTs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510124
Entities
People
- Ping Chi
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army