Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1). NF1 encodes aGTPase activating protein (GAP) for p21ras (Ras) called neurofibromin, and studies by us and others haveshown that the Ras signaling pathways are hyperactive in cells from NF1 patients. Neurofibromas arepathognomonic tumors that collectively affect 95% of NF1 patients. Neurofibromas are composed ofSchwann cells, endothelial cells, fibroblasts, degranulating, inflammatory mast cells, and pericytes/vascularsmooth muscle cells (VSMCs). Utilizing genetically engineered mice, Zhu et al (Science, 2002), found thathaploinsufficiency of Nf1 in cells in the tumor microenvironment was required for development ofneurofibromas.Our group previously provided the first genetic, cellular, and biochemical evidence that haploinsufficiencyof Nf1 alters Ras activity and cell fates in mast cells. We have now shown that Nf1+/- mast cells release adiverse number of growth factors and other molecules in response to stimulation via c-kit ligand and thatthese growth factors and molecules collectively promote angiogenesis, the alteration of extracellular matrixand cell growth. In both Nf1+/- murine models and primary cells from NF1 patients, we have now identifiedhaploinsufficient phenotypes in endothelial cells (ECs), VSMCs and fibroblasts that collectively promoteneoangiogenesis, collagen synthesis and alter the extracellular matrix. Further, we have identified keygrowth factors and biochemical pathways that regulate the haploinsufficient gains-in-function in each ofthese lineages and verified that the murine model closely recapitulates the human disease phenotypes.Identification of these multiple Nf1+/- cellular phenotypes and development of in vitro and in vivo modelsystems provide us a platform to test compounds alone or in combination that inhibit key Ras effectorkinases and growth factor receptors in neurofibromin deficient cells as a strategy to treat existing plexiformneurofibromas. Importantly, many of the kinases and molecular targets that we have discovered inneurofibromin deficient cells have also been identified in the treatment of more common cancers and provideus the opportunity to use existing preclinical compounds and phase 1-3 drugs that were developed for otheruses. Therefore, in this application, we are focusing on compounds that have already been extensivelyevaluated by pharmaceutical scientists in other model systems, thus allowing us to efficiently pursue multipletherapeutic targets. Finally, using a combination of PET and CT imaging, we now have the ability to imagethe development, growth, and metabolism of plexiform neurofibromas in genetically engineered mice in vivoas a function of time.
| 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 |
| Ferguson, Michael J; Rhodes, Steven D; Jiang, Li et al. (2016) Preclinical Evidence for the Use of Sunitinib Malate in the Treatment of Plexiform Neurofibromas. Pediatr Blood Cancer 63:206-13 |
