Abstract 705: Combinatorial therapeutic targeting of BMP2 and MEK in NF1-null malignant peripheral nerve sheath tumors

Abstract

Abstract Our lab has identified and validated bone morphogenetic protein 2 (BMP2) signaling pathways as a therapeutic target in malignant peripheral nerve sheath tumors (MPNSTs), independent of the NRAS and MEK1/2 regulation. BMP2/SMAD signaling is associated with enhanced motility and invasion, a hallmark feature of the biological aggressiveness of MPNSTs. We have shown that inhibition of BMP2 leads to decreased motility and invasiveness in MPNST cell lines. Consistent with our data, gene expression studies from NF1 patient tissue samples demonstrated that increased expression of BMP2 is associated with malignancy in NF1 patients. Ras-GAP related domain (GRD) is the most widely studied functional target of Nf1 implicated in tumorigenesis, however, therapeutic interventions targeting Ras activity have met with limited success. Our objective is to target the BMP2/SMAD pathway, involved in migration and invasion, in combination with MEK inhibitors to develop a novel therapeutic approach for treatment of MPNSTs. The mechanism by which NF1-deficiency leads to activation of BMP2 signaling pathways, and consequently increased cellular motility and invasion is unknown. Using NF1(+/-) and NF1 knockdown MPNST cell lines, we are investigating the transcriptional regulation of BMP2 by NF1 to identify signaling mechanisms downstream of NF1 mediating increase in BMP2 levels. We will present data showing that BMP2 is regulated at the level of transcript stability upon NF1 deficiency. We will identify and design a rational approach of targeting of the molecular components involved in stability of the BMP2 3′ UTR in MPNSTs. Furthermore, we will present a combinatorial approach that targets the growth and proliferative potential of MPNSTs by RAS-MEK inhibitors, along with motility and invasive capability by inhibition of the BMP2-Smad axis for better targeting of these tumors. The overall goal of our research is to use the regulation of BMP2 transcriptional control to define mechanism-based novel druggable targets that can be exploited in combinatorial therapies with RAS-MEK inhibitors to treat NF1-related tumors. Citation Format: Sidra Ahsan, Daochun Sun, Michael A. Tainsky. Combinatorial therapeutic targeting of BMP2 and MEK in NF1-null malignant peripheral nerve sheath tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 705. doi:10.1158/1538-7445.AM2015-705