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 #
5R01CA142928-04
Application #
8403560
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Yassin, Rihab R,
Project Start
2010-07-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
4
Fiscal Year
2013
Total Cost
$379,935
Indirect Cost
$167,086
Name
Research Institute of Fox Chase Cancer Center
Department
Type
DUNS #
064367329
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Prudnikova, T Y; Villamar-Cruz, O; Rawat, S J et al. (2016) Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells. Oncogene 35:2178-85
Kurimchak, Alison M; Shelton, Claude; Duncan, Kelly E et al. (2016) Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer. Cell Rep 16:1273-86
Villamar Cruz, Olga; Prudnikova, Tatiana Y; Araiza-Olivera, Daniela et al. (2016) Reduced PAK1 activity sensitizes FA/BRCA-proficient breast cancer cells to PARP inhibition. Oncotarget :
Reddy, Pavankumar N G; Radu, Maria; Xu, Ke et al. (2016) p21-activated kinase 2 regulates HSPC cytoskeleton, migration, and homing via CDC42 activation and interaction with β-Pix. Blood 127:1967-75
Rawat, Sonali J; Araiza-Olivera, Daniela; Arias-Romero, Luis E et al. (2016) H-ras Inhibits the Hippo Pathway by Promoting Mst1/Mst2 Heterodimerization. Curr Biol 26:1556-63
Prudnikova, Tatiana Y; Chernoff, Jonathan (2016) The Group I Pak inhibitor Frax-1036 sensitizes 11q13-amplified ovarian cancer cells to the cytotoxic effects of Rottlerin. Small GTPases :1-6
Kosoff, Rachelle E; Aslan, Joseph E; Kostyak, John C et al. (2015) Pak2 restrains endomitosis during megakaryopoiesis and alters cytoskeleton organization. Blood 125:2995-3005
Pandolfi, Ashley; Stanley, Robert F; Yu, Yiting et al. (2015) PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome. Blood 126:1118-27
Zeng, Yi; Broxmeyer, Hal E; Staser, Karl et al. (2015) Pak2 regulates hematopoietic progenitor cell proliferation, survival, and differentiation. Stem Cells 33:1630-41
O'Hagan, Kyle Leonard; Choi, Jinyong; Pryshchep, Olga et al. (2015) Pak2 Links TCR Signaling Strength to the Development of Regulatory T Cells and Maintains Peripheral Tolerance. J Immunol 195:1564-77

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