Neurofibromatosis type 1 (NF1) is a 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 malignant peripheral nerve sheath tumors - 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 heterozygous bone marrow-derived cells such as mast cells are a required component in pathogenesis, and that targeting signaling pathways in either Schwann cells or in mast cells might be of therapeutic benefit. The NF1 gene encodes a large protein, termed Neurofibromin, with GTPase Activating Protein (GAP) activity towards Ras. Complete or hemizygous loss of the NF1 gene leads to increased K-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 (Paks) play a vital role in K-ras signaling, in particular in the activation of te Erk and Akt pathways. As clinical-grade small molecules Pak inhibitors have recently emerged, there is a direct line from our proposed experiments to therapeutic application in NF1 syndrome, and perhaps also in other cancers driven by acquired, somatic NF1 mutations. In addition, we have used a new phospho-proteomic method to analyze the activity of hundreds of protein kinases in NF1-deficient cells, confirming known K-ras-activated signaling activity (e.g., elevated activity of Pak, Erk, and Akt/mTOR pathways) but also uncovering new potential candidates for targeted therapy. In this proposal, we postulate that Paks, which are required both for Erk and Akt/mTOR pathway activation downstream of K-ras, are uniquely suited as targets for therapy in NF1-driven plexiform neurofibromas and malignant peripheral nerve sheath tumors. Further, we posit that, should resistance emerge to anti-Pak agents, whole kinome analysis can be used to identify likely escape routes, allowing for more effective combinatorial therapy. Accordingly, we propose three aims: 1) We will determine the baseline status of the kinome in NF1-/- Schwann cells and mast cells, and how the kinome reprograms under pressure of Mek, Akt/mTOR, or Pak inhibition; 2) We will use mouse models of NF1 and Pak to determine the cellular basis for Pak's function in NF1-related tumors; and 3) We will determine the efficacy of specific small molecule Pak inhibitors in NF1 mouse models and xenografts, and assess the signaling responses elicited by such agents in vivo.

Public Health Relevance

NF1 is one of the most common inherited diseases and is often associated with serious health risks, including fatal cancers, yet no effective medical therapy exist for NF1-related malignancies. p21-activated kinases (Paks) are key regulators of two key signaling pathways downstream of K-ras, a protein that is activated as a result of loss of the NF1 gene, and blocking Pak may therefore 'kill two birds with one stone', effectively shutting off growth and survival signals in NF1-null Schwann cells and/or heterozygous mast cells. We have developed fine-tuned genetic models for studying Pak function in animals, and have unparalleled access to small molecule Pak inhibitors currently in clinical development, putting us in a unique position to explore the biological role of Paks in NF1 and to determine if these enzymes represent suitable targets for therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Microenvironment Study Section (TME)
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Yassin, Rihab R
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Research Institute of Fox Chase Cancer Center
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Chow, H Y; Dong, B; Valencia, C A et al. (2018) Group I Paks are essential for epithelial- mesenchymal transition in an Apc-driven model of colorectal cancer. Nat Commun 9:3473
Araiza-Olivera, D; Feng, Y; Semenova, G et al. (2018) Suppression of RAC1-driven malignant melanoma by group A PAK inhibitors. Oncogene 37:944-952
Semenova, G; Stepanova, D S; Dubyk, C et al. (2017) Targeting group I p21-activated kinases to control malignant peripheral nerve sheath tumor growth and metastasis. Oncogene 36:5421-5431
Zeng, Yi; Hahn, Seongmin; Stokes, Jessica et al. (2017) Pak2 regulates myeloid-derived suppressor cell development in mice. Blood Adv 1:1923-1933
Joseph, Giselle A; Lu, Min; Radu, Maria et al. (2017) Group I Paks Promote Skeletal Myoblast Differentiation In Vivo and In Vitro. Mol Cell Biol 37:
Semenova, Galina; Stepanova, Dina S; Deyev, Sergey M et al. (2017) Medium throughput biochemical compound screening identifies novel agents for pharmacotherapy of neurofibromatosis type 1. Biochimie 135:1-5
Semenova, Galina; Chernoff, Jonathan (2017) Targeting PAK1. Biochem Soc Trans 45:79-88
Lu, Hezhe; Liu, Shujing; Zhang, Gao et al. (2017) PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas. Nature 550:133-136
Prudnikova, Tatiana Y; Chernoff, Jonathan (2017) The Group I Pak inhibitor Frax-1036 sensitizes 11q13-amplified ovarian cancer cells to the cytotoxic effects of Rottlerin. Small GTPases 8:193-198
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 16:1273-1286

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