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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA168512-02
Application #
8561218
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$193,266
Indirect Cost
$9,487
Name
Sarc
Department
Type
DUNS #
186146911
City
Ann Arbor
State
MI
Country
United States
Zip Code
48106
Feng, Yong; Sassi, Slim; Shen, Jacson K et al. (2015) Targeting CDK11 in osteosarcoma cells using the CRISPR-Cas9 system. J Orthop Res 33:199-207
Monument, Michael J; Johnson, Kirsten M; McIlvaine, Elizabeth et al. (2014) Clinical and biochemical function of polymorphic NR0B1 GGAA-microsatellites in Ewing sarcoma: a report from the Children's Oncology Group. PLoS One 9:e104378
Choy, Edwin; Butrynski, James E; Harmon, David C et al. (2014) Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy. BMC Cancer 14:813
Kernstine, Kemp H; Moon, James; Kraut, Michael J et al. (2014) Trimodality therapy for superior sulcus non-small cell lung cancer: Southwest Oncology Group-Intergroup Trial S0220. Ann Thorac Surg 98:402-10
Sankar, Savita; Theisen, Emily R; Bearss, Jared et al. (2014) Reversible LSD1 inhibition interferes with global EWS/ETS transcriptional activity and impedes Ewing sarcoma tumor growth. Clin Cancer Res 20:4584-97
Zhang, Pingyu; Garnett, Jeannine; Creighton, Chad J et al. (2014) EZH2-miR-30d-KPNB1 pathway regulates malignant peripheral nerve sheath tumour cell survival and tumourigenesis. J Pathol 232:308-18
Sioletic, Stefano; Czaplinski, Jeffrey; Hu, Lan et al. (2014) c-Jun promotes cell migration and drives expression of the motility factor ENPP2 in soft tissue sarcomas. J Pathol 234:190-202
Chen, Eleanor Y; DeRan, Michael T; Ignatius, Myron S et al. (2014) Glycogen synthase kinase 3 inhibitors induce the canonical WNT/?-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma. Proc Natl Acad Sci U S A 111:5349-54
Krook, Melanie A; Nicholls, Lauren A; Scannell, Christopher A et al. (2014) Stress-induced CXCR4 promotes migration and invasion of ewing sarcoma. Mol Cancer Res 12:953-64
Jia, Bin; Choy, Edwin; Cote, Gregory et al. (2014) Cyclin-dependent kinase 11 (CDK11) is crucial in the growth of liposarcoma cells. Cancer Lett 342:104-12

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