In this application, entitled: NF: from animal models to therapeutics, we are requesting funds for continued support of the NF Center. We build on our preceding success in exploiting animal models to gain novel insight into tumor etiology and revealing the mast cell as a therapeutic target that is now in clinical trials. The Center supports a series of highly interactive and multidisciplinary studies aimed at (1) delineating the mechanisms underlying the two most common tumors in NF1: dermal and plexiform neurofibromas and (2) dissecting the unknown functions of neurofibromin in regulating adult endothelial and vascular smooth muscle function - two cell lineages critical for establishment of the tumor vasculature in neurofibromas, and in the development of NF1 vasculopathies. The Center is organized into a small Administrative Core, a Transgenic/Animal Core, and four Projects. The Transgenic/Animal Core (PI, Luis F. Parada) is responsible for breeding transgenic and knockout mice, genotyping, and for developing or importing additional mouse strains. Project 1 (PI, Luis F. Parada) is a continuation of a productive effort to study the molecular and cellular mechanisms by which NF1 mutation engenders plexiform neurofibromas and malignant peripheral nerve sheath tumors. Project 2 (PI, D. Wade Clapp) focuses on the signaling mechanisms that promote interplay between Nf1-/- Schwann cells and different heterozygous cell lineages identified in the tumor microenvironment in neurofibroma development and targeting these cell-cell interactions with FDA-approved therapeutics. Project 2 will also utilize human cells isolated from NF1 patients to verify that the observations in the murine model are faithfully recapitulated in the human system as a preclinical platform to identify therapeutic targets within the neurofibroma microenvironment. Project 3 (PI, David Ingram) will study the role of Nf1 in controlling endothelial and vascular smooth muscle/pericyte function. Project 4 (PI, Lu Q. Le) will investigate the etiology of dermal neurofibromas in mouse and proposes a clinical trial for treatment of human patients. Project 4 also proposes the establishment of a comprehensive NF1 clinic. Together, the proposed program of research promises to contribute to a better understanding of NF1-associated tumorigenesis at the molecular, cellular, and systems levels.
Neurofibromatosis type 1 is an incurable disease with an incidence of 1 in 3,500 live births. Hallmark features of NF1 include cafe au lait macules, and axillary and groin freckling, along with multiple peripheral and central nerve tumors including dermal and plexiform neurofibromas. The current research of the NF Center investigators will lead to a better understanding of the underlying molecular and cellular events that occur in NF1. 2P50NS052606-06/Project 1 PARADA, LUIS DESCRIPTION (provided by applicant): Neurofibromatosis type 1 is a genetic disease with wide ranging consequences on the afflicted individuals ranging from potential intellectual and cognitive deficits to appearance of idiopathic tumors in the peripheral nervous system collectively called neurofibromas. Over the past 12 years we have developed mouse models of NF1 with the objective of recapitulating a variety of the pathologic features seen in patients. This proposal continues and expands upon our experience in generating faithful genocopies of NF1-associated neurofibromas. In preceding work funded by this award, our scientific teams joined forces to test the hypothesis that NF1 haploinsufficiency outside the Schwann cell lineage provided critical contribution to plexiform neurofibroma development. This hypothesis emerged from studies with our mouse models and the outcome has revealed the importance of mast cells in contributing to the tumor phenotype and ultimately leading to clinical trials to block mast cell activity in patients. In the present application we propose to extend our mouse modeling capabilities to further understand the etiology of plexiform neurofibromas, to identify the source and etiology of dermal neurofibromas, and to use our MPNST models to seek out therapeutic opportunities.
In Specific Aim 1, we will employ tamoxifen-inducible ere driver lines and alternative approaches to better define the source of the cell of origin for plexiform neurofibromas and to define the temporal window of competence for tumor development.
In Specific Aim 2, we will expand on our recent development of a murine model for dermal neurofibromas and on the discovery that skin-derived precursors (SKPs) are the cell of origin for these tumors. We will use multiple techniques including the use of chick/quail embryo transplantation of neural tubes to examine whether the neural crest is the original source of these tumor-competent cells. We will also develop new valuable tamoxifen-inducible transgenic Cre driver lines to probe the neural crest-derived tissues for tumor potential. Finally, in Specific Aim 3, we will screen primary MPNST-derived tumor cells to undertake small chemical and RNAi high throughput screens. These screens aim to identify small molecule compounds and genes that are required for tumor cell proliferation and growth and that can become targets for therapeutics.
Neurofibromas and MPNSTs are incurable cancers that arise in Neurofibromatosis Type 1. We have created mutations in the NF1 gene in mice that allow us to generate faithful models of many of the disease pathologies. In this application, we use our genetic mouse models to study plexiform and dermal neurofibroma tumors to derive critical information for therapy development. We also propose strategies to discover novel potential therapeutic molecules for the treatment of MPNSTs.
|Bessler, Waylan K; Hudson, Farlyn Z; Zhang, Hanfang et al. (2016) Neurofibromin is a novel regulator of Ras-induced reactive oxygen species production in mice and humans. Free Radic Biol Med 97:212-222|
|Bessler, Waylan K; Kim, Grace; Hudson, Farlyn Z et al. (2016) Nf1+/- monocytes/macrophages induce neointima formation via CCR2 activation. Hum Mol Genet 25:1129-39|
|Ferguson, Michael J; Rhodes, Steven D; Jiang, Li et al. (2016) Preclinical Evidence for the Use of Sunitinib Malate in the Treatment of Plexiform Neurofibromas. Pediatr Blood Cancer 63:206-13|
|Stansfield, Brian K; Ingram, David A (2015) Clinical significance of monocyte heterogeneity. Clin Transl Med 4:5|
|Sanchez-Ortiz, Efrain; Cho, Woosung; Nazarenko, Inga et al. (2014) NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development. Genes Dev 28:2407-20|
|Chau, Vincent; Lim, S Kyun; Mo, Wei et al. (2014) Preclinical therapeutic efficacy of a novel pharmacologic inducer of apoptosis in malignant peripheral nerve sheath tumors. Cancer Res 74:586-97|
|Li, Fang; Downing, Brandon D; Smiley, Lucy C et al. (2014) Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo. Circulation 129:1213-24|
|Stansfield, Brian K; Bessler, Waylan K; Mali, Raghuveer et al. (2014) Ras-Mek-Erk signaling regulates Nf1 heterozygous neointima formation. Am J Pathol 184:79-85|
|Staser, Karl; Park, Su-Jung; Rhodes, Steven D et al. (2013) Normal hematopoiesis and neurofibromin-deficient myeloproliferative disease require Erk. J Clin Invest 123:329-34|
|Staser, Karl; Shew, Matthew A; Michels, Elizabeth G et al. (2013) A Pak1-PP2A-ERM signaling axis mediates F-actin rearrangement and degranulation in mast cells. Exp Hematol 41:56-66.e2|
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