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) patients develop vary number of benign Schwann cell tumors called neurofibromas for which there is no effective therapy available except surgery. New therapeutic strategies and new targets are urgently needed. We showed that: a) targeted genetic deletion of Runx1 & 3 simultaneously, or pharmacological inhibition of Runx function with a Runx1/Cbf? interaction inhibitor, Ro5-3335, inhibits mouse neurofibroma cell proliferation and induces cell apoptosis in vivo. b) five ERK-dependent and 6 ERK- independent miRs are deregulated >2 folds in mouse neurofibromas compared to normal mouse Schwann cells, c) miR-155 is regulated by ERK/AP-1. d) anti-miR-155 peptide nucleic acids (PNAs) inhibit mouse neurofibroma Schwann cell progenitor growth. e). Whole body knock out of miR-155 partially delays neurofibroma formation. We hypothesize that Runx1 & Runx3 and miR-155 are involved in neurofibroma formation, and inhibition of Runx/Cbf? and/or miR-155 expression will provide new therapies for neurofibroma. We plan to test this hypothesis by pursuing the following two specific aims using both genetically engineered mouse models and chemical/pharmacological inhibitors.
In Aim 1, we will genetically delete Runx1 & Runx3 simultaneously in Schwann cells and Schwann cell precursors by Cre-Loxp technique or inactivate Runx genes by inhibition of Runx/Cbf? interaction using a pharmacological inhibitor to determine Runx function in neurofibroma formation. We will also determine the mechanism(s) by which Runx1 & Runx3 regulate neurofibroma cell growth in vitro.
In Aim 2, we will inactivate ERK-dependent miR-155 in vivo by genetically mutation or chemically modified anti-miR-155 peptide nucleic acids (PNAs) that is delivered by a high efficacious nanoparticle system to determine the role of miR-155 in neurofibroma formation. We will dissect miR-155 pathways by determining how loss of Nf1 upregulates miR-155 and how miR-155 contributes to neurofibroma cell growth. We will determine if there is a causative link between miR-155 and Runx1 & Runx3. Overall, this proposal will provide mechanistic evidence of Runx1/3 and miR-155 function as oncogenes on neurofibroma formation and provide pre-clinical rationale for clinical trials.
Wu, Jianqiang Public Health Relevance Statement (Narrative attachment) Neurofibromatosis type 1 (NF1) is an inherited disease predisposing affected individuals to benign Schwann cell tumors called neurofibromas. Currently, prevention of neurofibromas is not possible. Surgery remains the mainstay of therapy. Unfortunately most of the patients experience tumors re-growth or recurrence after surgery. New therapeutic strategies and new targets for neurofibroma treatment are urgently needed. This proposal will test the therapeutic effect of a Runx1/Cbf? interaction inhibitor, Ro5-3335, on mouse neurofibromas. Ro5-3335 is a promising compound that will potentially lead to a unique, targeted treatment of neurofibroma as well as other Runx1 overexpressing cancers. We all also test the effects on neurofibromas by inhibiting microRNA-155 expression or Runx inactivation in genetically engineered neurofibroma mouse models. The proposed nanoparticle-based antagomiR therapeutic testing will provide proof-of-concept for in vivo antagomiR therapy in neurofibroma patients. These results will provide pre-clinical rationale for clinical trials.