Neurofibromatosis type 2 (NF2) is a debilitating and medically-incurable tumor disorder of the nervous system caused by inactivating mutations of the gene that encodes merlin tumor suppressor. NF2 patients develop multiple schwannomas throughout the nervous system for which there is no pharmacological treatment. Patients undergo debilitating repeated invasive surgeries to remove or debulk tumors growing along the nerves, risking permanent nerve damage. Growing evidence implicates protein oxidation by reactive nitrogen species as a major contributor to tumor growth, but the specific oxidative modifications and target proteins that mediate tumorigenic activity are unknown. Our goals are to reveal novel mechanisms that mediate dysregulation of cell proliferation in NF2 and identify specific oxidatively modified proteins that may serve as tumor-directed, non-invasive therapeutic targets for NF2 and other tumors. Our exciting preliminary findings revealed that one such oxidative modification, tyrosine (Tyr) nitration, selectively supports schwannoma cell survival and contributes to schwannoma metabolic phenotype by decreasing oxidative phosphorylation complex IV levels and activity, while increasing glycolysis and glutaminolysis. Further, we identified 31 endogenous nitrated proteins in schwannomas, including Hsp90, which we showed decreases mitochondrial respiration when nitrated, the transcription factor GABP, responsible for the regulation of complex IV expression, and 5 tumorigenic proteins that participate in signaling pathways that are deregulated in NF2. We will thus test the hypothesis that selective Tyr nitration of proteins in NF2 dysregulates mitochondrial respiration and signaling pathways that are responsible for metabolic reprogramming, which in turn supports proliferation and survival of schwannomas. Driven by strong preliminary data we will elucidate the mechanism by which Tyr nitration regulates complex IV expression and activity (Aim 1); and determine the specific nitrated proteins and mechanisms that promote schwannoma metabolic reprogramming and growth (Aim 2). The proposed research is highly innovative, because it will identify concept-advancing and exceptional novel targets for drug development that are present in tumors but not in normal tissues. Furthermore, these findings are of high significance to human disease, since they may pave the way to completely new and efficacious treatment modalities, not only for NF2, but also for other solid tumors in the future.
We have discovered a new Achilles Heel for attacking Neurofibromatosis (type 2), a debilitating hereditary disorder characterized by the growth of tumors of the nervous system affecting thousands of children and young patients. We are evaluating how to exploit this vulnerability to develop treatments targeting tumors like those growing in neurofibromatosis without affecting healthy surrounding tissues.
