Neurofibromatosis type I (NF1) affects 1 out of 3500 individuals, who have an approximate 10% lifetime risk of developing a NF1 related malignancy. Loss of NF1 provokes a variety of clinical manifestations, some of which are devastating. Life threatening manifestations can arise from the progression to malignant peripheral nerve tumors (MPNSTs). Currently the only treatments are only rarely effective. Molecularly, NF1 results in the activation of the Ras oncogene and in some cases a rise in cAMP levels. Ras activation results in the stimulation of two signaling pathways which mediate oncogenesis: the class 1 PI3K and RAF kinase signaling pathways. Activation of the PI3K pathway leads to the inhibition of the Tuberous Sclerosis Complex (TSC) tumor suppressor (TSC1/2) through phosphorylation of TSC2. In turn, activation of the RAF kinase pathway induces the sequential stimulation of two kinases that have been shown to phosphor/late TSC2 at distinct phosphorylation sites, raising the possibility that the RAF pathway may also mediate inhibition of TSC1/2 in NF1. Inhibition of TSC1/2 increases the GTP-bound form of Rheb, which stimulates the mammalian Target Of Rapamycin (mTOR), a large protein kinase. mTOR mediates the phosphorylation of a number of downstream substrates implicated in cell growth, such as S6 kinase 1 (S6K1) and initiation factor 4E binding protein (4E-BP1). Studies in Drosophila and mice argue that the effects on growth in a TSC1/2 deficient setting are largely mediated through S6K1. Moreover the mTOR/S6K1 signaling pathway is also regulated by nutrients, and we have recently found that the nutrient pathway is controlled through class 3 PI3K (hVps34), which itself is regulated by protein kinase A (PKA). As loss of NF1 function also leads to a rise in PKA signaling, our model is that activation of PKA in NF1 mutant cells may drive S6K1 activation independent of the class 1 PI3K or RAF. Here we have outlined experiments which will allow us to (1) discern the contribution of the PI3K and RAF pathways in NF1, (2) the importance of PKA activation, mediated by hVps34, in NF1, and (3) the role of S6K1 in mediating these neoplastic response in NF1. In the long term, working with the members of the Cincinnati Center for Neurofibromatosis Research, we propose to develop targeted therapies against specific cellular proteins known to be deregulated in NF1 pathologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS057531-05
Application #
8382448
Study Section
Special Emphasis Panel (ZNS1-SRB-G)
Project Start
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$392,951
Indirect Cost
$19,301
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Maertens, Ophélia; McCurrach, Mila E; Braun, Benjamin S et al. (2017) A Collaborative Model for Accelerating the Discovery and Translation of Cancer Therapies. Cancer Res 77:5706-5711
Wu, Jianqiang; Keng, Vincent W; Patmore, Deanna M et al. (2016) Insertional Mutagenesis Identifies a STAT3/Arid1b/?-catenin Pathway Driving Neurofibroma Initiation. Cell Rep 14:1979-90
Jousma, Edwin; Rizvi, Tilat A; Wu, Jianqiang et al. (2015) Preclinical assessments of the MEK inhibitor PD-0325901 in a mouse model of Neurofibromatosis type 1. Pediatr Blood Cancer 62:1709-16
Haworth, Kellie B; Leddon, Jennifer L; Chen, Chun-Yu et al. (2015) Going back to class I: MHC and immunotherapies for childhood cancer. Pediatr Blood Cancer 62:571-6
Wu, J; Patmore, D M; Jousma, E et al. (2014) EGFR-STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors. Oncogene 33:173-80
Watson, Adrienne L; Anderson, Leah K; Greeley, Andrew D et al. (2014) Co-targeting the MAPK and PI3K/AKT/mTOR pathways in two genetically engineered mouse models of schwann cell tumors reduces tumor grade and multiplicity. Oncotarget 5:1502-14
Moriarity, Branden S; Rahrmann, Eric P; Beckmann, Dominic A et al. (2014) Simple and efficient methods for enrichment and isolation of endonuclease modified cells. PLoS One 9:e96114
Brundage, M E; Tandon, P; Eaves, D W et al. (2014) MAF mediates crosstalk between Ras-MAPK and mTOR signaling in NF1. Oncogene 33:5626-36
Prada, Carlos E; Jousma, Edwin; Rizvi, Tilat A et al. (2013) Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol 125:159-68
Rahrmann, Eric P; Watson, Adrienne L; Keng, Vincent W et al. (2013) Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis. Nat Genet 45:756-66

Showing the most recent 10 out of 21 publications