Title: p21-activated kinases as new therapeutic targets in neurofibromatosis type 1. Project Summary: Neurofibromatosis type 1 (NF1) is a relatively common inherited disease syndrome caused by germline mutations in the NF1 gene. About one third of NF1 patients develop diffuse, plexiform neurofibromas that can transform to a malignant peripheral nerve sheath tumor - a cancer that is frequently fatal. Remarkably, in human tumors and in mouse models of NF1, neurofibromas almost invariably contain Nf1-null Schwann cells and Nf1 heterozygous mast cells. Transplanting such NF1-prone mice with wild- type bone marrow prevents tumorigenesis, implying that bone marrow derived cells such as mast cells are a required component in pathogenesis, and that targeting signaling pathways in either Schwann cells or mast cells might be of therapeutic benefit. The NF1 gene encodes a large protein with GTPase Activating Protein (GAP) activity towards Ras. Complete or hemizygous loss of the NF1 gene leads to increased Ras activity in both Schwann cells and mast cells, with concomitant activation of downstream effectors that promote proliferation and changes in cell shape and movement. Recently, we have shown that p21-activated kinases play an important role in activating an Erk-mediated proliferation and a p38- mediated motility pathway downstream of Ras in Nf1-deficient mast cells. We postulate that loss of Pak function will diminish activation of key Ras effector pathways in Nf1-deficient Schwann cells as well, and thus could benefit patients with NF1. We propose three aims: 1) We will identify the key substrates of group A Paks in mast cells that affect cell motility;2) Using pharmacologic and genetic means to disable Paks in Schwann cells derived from Nf1-deficient mice, we will determine if loss of Pak function reverses the activation of MAPK and cytoskeletal alterations in vitro;and 3) We will cross Krox20-cre/Nf1flox/- mice, which develop malignant peripheral nerve sheath tumors, with Pak1 knock out mice, or transplant such NF1 mice with Pak1-/- bone marrow cells, to determine if loss of Pak1, globally or in bone marrow derived cells, affects disease progression. The proposed studies will not only increase our understanding of cardinal cancer-relevant signaling pathways, but could establish the Paks as suitable targets for therapeutic intervention in this otherwise untreatable disease.

Public Health Relevance

to Public Heath: p21-activated kinases (Paks) are key regulators of signaling downstream of Ras, a protein that is activated as a result of loss of the NF1 gene. Currently, there are no effective therapies for NF1-related malignancies. We have developed genetic models for studying Pak function in animals, as well as the first specific chemical inhibitor of these enzymes;for these reasons, we are in a unique position to explore the biological role of Paks in NF1 and to determine if these enzymes represent suitable targets for therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA142928-05
Application #
8609553
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Yassin, Rihab R,
Project Start
2010-07-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2014
Total Cost
$363,768
Indirect Cost
$159,976
Name
Research Institute of Fox Chase Cancer Center
Department
Type
DUNS #
064367329
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Radu, Maria; Semenova, Galina; Kosoff, Rachelle et al. (2014) PAK signalling during the development and progression of cancer. Nat Rev Cancer 14:13-25
Baker, Nicole M; Yee Chow, Hoi; Chernoff, Jonathan et al. (2014) Molecular pathways: targeting RAC-p21-activated serine-threonine kinase signaling in RAS-driven cancers. Clin Cancer Res 20:4740-6
Kelly, Mollie L; Astsaturov, Artyom; Rhodes, Jennifer et al. (2014) A Pak1/Erk signaling module acts through Gata6 to regulate cardiovascular development in zebrafish. Dev Cell 29:350-9
Dorrance, Adrienne M; De Vita, Serena; Radu, Maria et al. (2013) The Rac GTPase effector p21-activated kinase is essential for hematopoietic stem/progenitor cell migration and engraftment. Blood 121:2474-82
Aslan, Joseph E; Itakura, Asako; Haley, Kristina M et al. (2013) p21 activated kinase signaling coordinates glycoprotein receptor VI-mediated platelet aggregation, lamellipodia formation, and aggregate stability under shear. Arterioscler Thromb Vasc Biol 33:1544-51
Aslan, Joseph E; Baker, Sandra M; Loren, Cassandra P et al. (2013) The PAK system links Rho GTPase signaling to thrombin-mediated platelet activation. Am J Physiol Cell Physiol 305:C519-28
Radu, Maria; Chernoff, Jonathan (2013) An in vivo assay to test blood vessel permeability. J Vis Exp :e50062
Itakura, Asako; Aslan, Joseph E; Kusanto, Branden T et al. (2013) p21-Activated kinase (PAK) regulates cytoskeletal reorganization and directional migration in human neutrophils. PLoS One 8:e73063
Arias-Romero, Luis E; Villamar-Cruz, Olga; Huang, Min et al. (2013) Pak1 kinase links ErbB2 to ?-catenin in transformation of breast epithelial cells. Cancer Res 73:3671-82
Kelly, Mollie L; Astsaturov, Artyom; Chernoff, Jonathan (2013) Role of p21-activated kinases in cardiovascular development and function. Cell Mol Life Sci 70:4223-8

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