Therapeutic Potential of Ezrin Inhibition in NF2-Associated Schwannomas
Abstract
This proposal takes advantage of the complementary expertise of Drs. Jeremie Vitte, Marco Giovannini, (UCLA) and collaborator Andrea McClatchey (MGH/Harvard). It addresses the areas of emphasis of the FY22 NFRP: NF2-related areas and Target identification, drug discovery. The main characteristic of neurofibromatosis type 2 (NF2) is the development of schwannoma, tumors that form around the auditory and other cranial and spinal nerves. Depending on location and size, these tumors can cause a range of neurological symptoms including deafness, tinnitus, dizziness, pain, paralysis and even death due to brain compression. Current treatment of schwannomas is largely limited to surgical resection, which carries some risks such as cerebrospinal fluid leak, meningitis, bleeding, cerebral edema, and even death. This lack of therapeutic options reflects, at least in part, our limited knowledge of the biology explaining the development of schwannomas. Because schwannomas grow slowly, they are difficult to treat. Standard chemotherapies targeting fast diving cells, that are used as cancer treatment, do not usually work for these tumors. NF2 schwannomas are characterized by loss of the merlin protein due to mutations in the NF2 gene in Schwann cells, cells that wrap around neurons in nerves. Optimally, a treatment for NF2 schwannoma would exploit features specific of NF2 schwannoma cells and eliminate the broad consequences of merlin loss. We discovered that blocking ezrin, a protein in the same family as merlin, fixed some of the issues caused by merlin loss in Schwann cells. Here, we propose testing the idea that blocking ezrin stops schwannoma development, and therefore could represent a new therapeutic target for NF2 tumors. The goals of this 1-year proposal are to test this idea by evaluating the effect of combined merlin/ezrin loss in cells and in mice. A new mouse model will allow us to inactivate simultaneously merlin and ezrin, and study the consequences on tumor development by counting cells in the tumors. Schwann cells isolated from these mice will be used to evaluate the effect of merlin/ezrin loss on the NF2-specific features and proliferation. In the second part, we will use small molecules to block ezrin function in Schwann cells and mouse with merlin loss. In these multiple experiments, if cells grow slower or loose NF2 features and tumors are smaller after ezrin loss or blockage, our initial idea that ezrin can be a therapeutic target for NF2 tumors will be validated. The successful completion of this work will provide the NF2 research and clinical community with outstanding new tools to explore blocking ezrin as a new possible treatment for NF2 schwannomas. We believe that these studies will also have a strong impact on the NF2 field in the long term with the potential to use this therapeutic approach for other NF2-related tumors or in conjunction with other treatments.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310404
Entities
People
- Jeremie Vitte
Organizations
- United States Army
- University of California, Los Angeles