MiR-155 and RUNX function in neurofibroma tumorigenesis and therapy

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Principal Investigator/Program Director (Last, first, middle): Wu, Jianqiang Project summary Using technical language, briefly describe the research design and rationale for achieving the stated goals Neurofibromatosis type 1 (NF1) is an inherited disease predisposing affected individuals to benign Schwann cell tumors called plexiform neurofibromas (PNFs). Currently, prevention of PNFs is not possible, partly because the molecular mechanisms of tumorigenesis are not fully understood. Surgery remains the mainstay of therapy for PNFs. The FDA approved cytostatic MEK inhibitor, Selumetinib (Koselugo), shrinks tumor in 70% of individuals but tumors regrow after stopping drug treatment. Therefore, new therapeutic strategies and targets for the treatment of neurofibroma are urgently needed. The endoplasmic reticulum (ER) stress response pathways play pivotal roles in tumor growth and therapy in several cancers but remain unstudied in neurofibroma. Targeting these ER stress pathways might provide a novel therapy for PNF patients. Our new preliminary data show that: a) All three ER stress signaling pathways are activated in both mouse and human PNFs compared to controls. b) Knock down of protein kinase RNA-like endoplasmic reticulum kinase (PERK) by shRNA decreases neurofibroma like tumor number in a cell transplantation model in nude mice. c) Pharmacological inhibition of valosin-containing protein (VCP) together with a MEK inhibitor (MEKi) decreases cell proliferation, increases cell apoptosis and induces protein ubiquitination. Our central hypothesis is that loss of Nf1 in SC/SCPs leads to PNF formation by driving Runx- and VCP-regulated proteostasis to adapt to ER stress signaling, so that targeting proteostasis provides cytotoxic therapy for PNF patients. Two specific aims are proposed: In aim 1, we will determine if and how Runx and VCP regulate protein synthesis and degradation to maintain proteostasis so that Nf1-/- SC/SCPs adapt to ER stress, thereby driving PNF initiation and growth. In aim 2, we will test whether overwhelming irresolvable ER stress by targeting VCP (alone or in combination with MEKi) provides cytotoxic and, thus, durable control of PNF growth, and determine the mechanism of action. Overall, this proposal will provide mechanistic evidence of Runx1/3 and possible VCP- dependent proteostasis and adaptive ER stress signaling functions as oncogene on PNF formation and provide pre-clinical rationale for MEK-independent clinical trials.