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Access Type

WSU Access

Date of Award

January 2016

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Cancer Biology

First Advisor

Michael A. Tainsky

Abstract

Neurofibromatosis type I (NF1)-deficient malignant peripheral nerve sheath tumor (MPNST) is an aggressive tumor for which the standard treatment is surgical removal with wide margins, often leaving behind cancer cells needing chemotherapy. RAS-GRD is the most widely studied functional target of NF1 implicated in tumorigenesis, however, therapeutic interventions targeting RAS activity have met with limited success. Using gene expression profiling, our lab identified BMP2-SMAD1/5/8 signaling pathway as a therapeutic target in MPNSTs, independent of the NRAS and MEK1/2 regulation. The overall goal of my research was to validate the significance of BMP2 in MPNSTs in novel cellular models, study the combinatorial effects of BMP2 and MEK1/2 inhibition, and use the regulation of BMP2 transcriptional control to define mechanism-based rational targets of BMP2 signaling, to treat NF1-related tumors.

Biological aggressiveness of MPNSTs is characterized by its highly motile and invasive nature. I presented a unique approach that targets not only the motility and invasive capability but also growth and proliferative potential of MPNSTs, by inhibition of BMP2-SMAD1/5/8 and RAS-MEK1/2-ERK1/2 signaling pathways in MPNST cell lines. By using physiologically relevant cell models that simulate MPNST condition in vivo, I have shown that combinatorial targeting of BMP2 and MEK1/2 pathways results in reversal of malignant features of MPNST cell lines. Additionally, I have identified a novel regulatory mechanism by which NF1 mediates BMP2 transcript stability. The targeted inhibition of the molecular components involved in stability of the Bmp2 3’ UTR by NF1, represents an alternative approach of genetic targeting in MPNSTs. In summary, I have presented two independent methodologies of therapeutically targeting BMP2-SMAD1/5/8 signaling in MPNSTs.

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