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 #
1U54CA168512-01
Application #
8395374
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (M1))
Project Start
2012-09-26
Project End
2017-08-31
Budget Start
2012-09-26
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$214,971
Indirect Cost
$9,999
Name
Sarc
Department
Type
DUNS #
186146911
City
Ann Arbor
State
MI
Country
United States
Zip Code
48106
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