Posted May 16, 2018
Cristina Fernandez-Valle, Ph.D., University of Central Florida

Neurofibromatosis type 2 (NF2) is a genetic syndrome caused by the loss of function of the NF2 gene that encodes the Merlin tumor suppressor protein. The loss of Merlin causes Schwann cells (cells that wrap around nerves, providing protection and support) to form noncancerous tumors called schwannomas on cranial, spinal, and peripheral nerves. The signs and symptoms vary and depend on the size, location, and number of schwannomas. Complications of tumor growth may cause hearing loss, balance dysfunction, vision problems, weakness in arms and legs, fluid buildup in the brain, and death. To date there are no US Food and Drug Administration (FDA)-approved therapies that target schwannoma cells in order to reduce the complications associated with NF2. Treatment options for schwannomas in NF2 patients are often limited to surgery, which is not ideal, as serious adverse effects such as nerve damage are often associated with the tumor removal.

With support from an FY14 Neurofibromatosis Research Program (NFRP) Investigator-Initiated Research Award, Dr. Cristina Fernandez-Valle and her laboratory set out to evaluate multiple FDA-approved Src and c-Met inhibitors for their ability to disable the Merlin-deficient Schwann cells that are responsible for forming schwannomas. Src and c-Met kinases are activated in NF2-associated schwannomas, and recent data suggest that drugs targeting these proteins may be good candidates for treating NF2 tumors. There are a number of FDA-approved drugs targeting Src and c-Met that are used to treat other diseases. If these drugs could be repurposed for the treatment of schwannomas, it would accelerate the development and realization of these therapies for NF2 patients.

Dr. Fernandez-Valle and her colleagues investigated FDA-approved drugs targeting Src and c-Met alone and in combination treatments to determine if they could be repurposed for schwannoma treatment. When Merlin-deficient mouse Schwann cells were treated singularly with the c-Met inhibitor, cabozantinib, or with one of the Src inhibitors, ponatinib, dasatinib or saracatinib, they displayed reduced viability. The molecular targets of the drugs were proteins related to the cell cycle, as a robust arrest at the G1 phase of the cell cycle in Merlin-deficient Schwann cells was detected. When the cells were treated with a combination therapy of cabozantinib and saracatinib, apoptosis (cell death) was selectively induced in Merlin-deficient Schwann cells but not in wildtype (normal) Schwann cells. The combination treatment also reduced growth of Merlin-deficient mouse Schwann cells in a mouse model by 80% compared to vehicle treatment. Human schwannoma cells with NF2 mutations displayed a 40% decrease in cell viability with the combination treatment when compared to control treatment.

The success of these repurposed drugs in inhibiting Merlin-deficient Schwann and schwannoma cell proliferation warrants future studies in mouse models of NF2 to further address the possible use of these drugs as effective therapies for NF2 patients. Also, these results indicate that the combined inhibition of Src and c-Met can trigger Schwann cell death, which suggests a vulnerability in schwannomas that could potentially be targeted for the development of much needed NF2 therapies.

Publications:

Fuse MA, Klingeman Plati S, Burns SS, Dinh CT, Bracho O, Yan D, Mittal R, Shen R, Soulakova JN, Copik AJ, Liu XZ, Telischi FF, Chang LS, Franco MC, and Fernandez-Valle C. 2017. Combination Therapy With c-Met and Src Inhibitors Induces Caspase-Dependent Apoptosis of Merlin-Deficient Schwann Cells and Suppresses Growth of Schwannoma Cells. Mol Cancer Ther. 16(11):2387-2398.

Petrilli AM, Garcia J, Bott M, Klingeman Plati S, Dinh CT, Bracho OR, Yan D, Zou B, Mittal R, Telischi FF, Liu XZ, Chang LS, Welling DB, Copik AJ, and Fern�ndez-Valle C. 2017. Ponatinib promotes a G1 cell-cycle arrest of merlin/NF2-deficient human schwann cells. Oncotarget. 8:31666-31681. doi: 10.18632/oncotarget.15912.

Link:

Public and Technical Abstracts: In Vivo Validation of High-Throughput Drug Screen Results for NF2

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