Malignant peripheral nerve sheath tumors (MPNSTs) are genetically complex soft-tissue sarconnas that have one of the highest risks of sarcoma-specific deaths, which could be attributed to its limited responses to conventional chemo- and radiotherapies as well as its invasive growth that often prevent complete surgical resection. These clinical observations emphasize the urgent need for novel therapies based on a greater understanding of molecular and cellular pathogenesis of MPNST. More than 50% of MPNSTs are identified in individuals afflicted with neurofibromatosis type 1 (NFI). NF1-associated MPNST often arises within a subpopulation of benign peripheral nerve sheath tumor (PNST), plexiform neurofibroma (PNF), which is hypothesized as a congenital lesion caused by NF1 inactivation in multipotent neural crest stem cells (NCSCs) during nerve development. Thus, NF1-associated MPNST may represent the only sarcoma with a defined developmental basis and a critical benign precursor lesion. As such prevention treatments could be a reasonable expectation. Recent studies showed that loss of NF1 activates Ras-mediated extracellularsignal- regulated/mitogen-activated protein kinase (ERK/MAPK) signaling pathway in MPNST cell lines. However, our preliminary studies using genetically engineered mouse (6EM) models showed that despite consistent activation of Erk/MAPK in pre-neoplastic and benign lesions, nearly half of MPNSTs exhibited no Erk/MAPK activation. The overall goal of this proposal is to determine whether multipotent NCSCs are the cell-of-ongin for a subset of plexiform neurofibromas that have high potentials for recurrence and malignant transformation (Aim 1). Furthermore, we attempt to determine whether prior to MPNST, there is a critical therapeutic window(s) in which an ERK/MAPK pathway inhibitor (MEKi) can prevent PNF and MPNST formation (Aim 2). Finally, we attempt to define a subset of MPNSTs that will respond to MEKi (Aim 3). All three aims provide a pathway leading to either a prevention strategy and/or therapeutic strategy based on modern genetic laboratory investigation of appropriate human tissues as well as further development of mouse models of this disease process.
Malignant peripheral nerve sheath tumors (MPNSTs) carry one ofthe highest sarcoma-specific deaths. The experiments proposed in this application not only will establish the concept regarding the progressive pathogenesis of NF1-associated MPNST, but also contribute to the development of prevention and treatment strategies for these devastating human tumors based on modern genetic inquiry.
|Nakayama, Robert; Zhang, Yi-Xiang; Czaplinski, Jeffrey T et al. (2016) Preclinical activity of selinexor, an inhibitor of XPO1, in sarcoma. Oncotarget 7:16581-92|
|Goldstein, Seth D; Trucco, Matteo; Bautista Guzman, Wendy et al. (2016) A monoclonal antibody against the Wnt signaling inhibitor dickkopf-1 inhibits osteosarcoma metastasis in a preclinical model. Oncotarget 7:21114-23|
|Schaefer, Inga-Marie; Fletcher, Christopher Dm; Hornick, Jason L (2016) Loss of H3K27 trimethylation distinguishes malignant peripheral nerve sheath tumors from histologic mimics. Mod Pathol 29:4-13|
|MariÃ±o-EnrÃquez, AdriÃ¡n; BovÃ©e, Judith V M G (2016) Molecular Pathogenesis and Diagnostic, Prognostic and Predictive Molecular Markers in Sarcoma. Surg Pathol Clin 9:457-73|
|Tang, Qin; Moore, John C; Ignatius, Myron S et al. (2016) Imaging tumour cell heterogeneity following cell transplantation into optically clear immune-deficient zebrafish. Nat Commun 7:10358|
|Bobowski, Nina P; Baker, Laurence H (2016) The University of Michigan Sarcoma Survivorship Clinic: Preventing, Diagnosing, and Treating Chronic Illness for Improved Survival and Long-Term Health. J Adolesc Young Adult Oncol 5:211-4|
|Koehler, K; Liebner, D; Chen, J L (2016) TP53 mutational status is predictive of pazopanib response in advanced sarcomas. Ann Oncol 27:539-43|
|Bid, Hemant K; Phelps, Doris A; Xaio, Linlin et al. (2016) The Bromodomain BET Inhibitor JQ1 Suppresses Tumor Angiogenesis in Models of Childhood Sarcoma. Mol Cancer Ther 15:1018-28|
|Simon, Priscilla S; Bardhan, Kankana; Chen, May R et al. (2016) NF-ÎºB functions as a molecular link between tumor cells and Th1/Tc1 T cells in the tumor microenvironment to exert radiation-mediated tumor suppression. Oncotarget 7:23395-415|
|De Rienzo, Assunta; Archer, Michael A; Yeap, Beow Y et al. (2016) Gender-Specific Molecular and Clinical Features Underlie Malignant Pleural Mesothelioma. Cancer Res 76:319-28|
Showing the most recent 10 out of 86 publications