Two decades have passed since human geneticists discovered Merlin as the tumor suppressor underlying Neurofibromatosis Type II. Unfortunately, NF2 patients are still suffering from this devastating disease due to the lack of effective targeted therapeutics.

Compared to NF1, the molecular function of the NF2/Merlin tumor suppressor protein is less well understood, which hampers the development of effective therapeutics. Recently, exciting studies using multiple experimental models have functionally linked NF2/Merlin to the Hippo signaling pathway, a cell signaling pathway that normally controls organ size in all animals. The Hippo pathway comprises several tumor suppressors that act in a kinase cascade that ultimately phosphorylates and inactivates the oncoprotein Yki (Drosophila)/YAP (mammals). The functional link between NF2/Merlin and the Hippo pathway raises the exciting possibility that components of the Hippo pathway such as YAP may serve as ideal drug targets for the treatment of Neurofibromatosis Type II.

Most recently, my laboratory identified Verteporfin, a Food and Drug Administration-approved drug currently used for the treatment of macular degeneration, as the first small molecule inhibitor of YAP. Verteporfin suppresses YAP activity both in vitro and in mouse models, including a mouse model of NF2 inactivation in the liver. This study provides the proof of principle that inhibiting YAP activity is a promising and pharmacologically viable strategy for the intervention of mammalian tumors caused by YAP activation including NF2.

The central goal of this proposal is to develop molecular targeted therapies against NF2. Building on our recent demonstration of Verteporfin's ability to suppress NF2-deficient phenotypes in the liver, we will first test whether Verteporfin is effective in tissue contexts that are more relevant to NF2 disease, such as schwannomas and ependymomas. The second objective of this proposal is to identify additional drug targets besides YAP that can be exploited for NF2 therapeutics. Once such targets are identified, chemical screens can be conducted to discover their small molecule inhibitors. The identification of these additional drug targets will greatly enhance the possibility of combinatorial therapies against NF2 in the future.

In summary, since there are no drugs in preclinical testing that specifically target the Merlin tumor suppressor, this application represents an important and much-needed "de novo" approach for the development of effective therapeutics for the treatment of Neurofibromatosis Type II.