Identification of therapeutic windows for NF1-related malignant peripheral nerve

Sarc, Ann Arbor MI

Investigators

Linked publications & trials

Abstract

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.