p21-activated kinase 1 and 2 as therapeutic targets of the NF1 microenvironment Neurofibromatosis Type I (NF1) is characterized by neurofibromas consisting of NF1-null schwann cells and a mixture of Nf1-heterozygous stromal cells. Cross talk between mutant stromal cells and schwann cells promotes angiogenesis, collagen deposition and mast cell infiltration. Therapeutic targeting of the c-kit signaling pathway in mas cells could potentially reduce neurofibromin formation. Nf1-heterozygous mast cells are hyperactive for c-kit receptor mediate migration, proliferation and chemoattraction to Schwann cells. By disrupting hyperactive c-kit signaling in mast cells and regulating the tumor microenvironment, we can disrupt tumor growth in NF1 and other tumors dependent on mast cells. Recent discoveries in our lab demonstrates that enhanced mast cell signaling downstream of Nf1 requires p21-activated kinase 1 (PAK1) for enhanced migration and proliferation in vitro and in vivo. Since mast cells promote tumor growth in NF1, and their deletion impairs tumor progression, PAK1 inhibition in mast cells is a desirable target for NF1 through small molecule inhibitors designed to inhibit Group A Pak family kinases (Pak1-3). Our preliminary studies show that another isoform, PAK2 is the dominant isoform in mast cells. This isoform has the opposite phenotype to PAK1 in mast cells in another mast cell receptor pathway. The role of Pak2 in c-kit/SCF/NF1 signaling axis has yet to be studied. The objective in our study is identify in vitro and in vivo if Pak2 functions opposite of Pak1 in c-kit/Nf1 signaling, and if so, identify the signaling differences. In vitro experiments on Pak2-deficient primary mast cells will measure mast cell migration, adhesion, proliferation and MAPK signaling to elucidate the differences between Pak1 and Pak2. With small molecule inhibitors being developed against Group A Paks, it is critical to identify differences that could result in reduced potency or potential side effects. In vivo studie using dermal mast cell migration to SCF and bone marrow transplantation in NF1 will elucidate the role that Pak2 plays in c-kit signaling in skin and in tumor microenvironment cells. By replacing Nf1 wildtype bone marrow with Nf1-heterozygous~Pak1-/- or Pak2-/- bone marrow in mice prone to neurofibromas, we will identify if they play opposing roles to support tumor growth. This research is necessary to understand potential side effects of inhibiting multiple Pak kinases simultaneously in NF1 patients wih drug inhibitors.

Public Health Relevance

Neurofibromatosis Type I (NF1) is a tumor whose growth is dependent on surrounding non-tumorigenic cells and growth factors secreted from them. Targeting these cells; rather than tumor cells could halt tumor growth; with minimal drug resistance and fewer side effects. We propose in our work that pharmacologic interference with this communication network will disrupt NF1; and prevent childhood cancer from progressing.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F09-P (21))
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Schmidt, Michael K
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
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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