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New Research Investigates Potential Therapeutics for NF2

By Salvatore La Rosa, VP Research and Development

Early investments from the Children’s Tumor Foundation are paying off and delivering innovative and impactful research. It’s great to see research moving forward thanks to the support of both private and public funding. Our philosophy of betting on high-risk high-reward projects is proving successful and will eventually help us realize our vision of ending NF.

Cristina Fernandez-Valle, PhD, one of the Synodos for NF2 researchers, received a Contract Award from the Children’s Tumor Foundation in 2013 to develop new drug therapeutics for NF2. The CTF award allowed Dr. Fernandez-Valle to collaborate with a technology company called CENIX Bioscience, a contract research organization specializing in advanced applications of RNA interference (RNAi) gene silencing combined with high content phenotyping in cultured cells in vitro and in animals in vivo. The collaboration generated insights on new mechanisms by which NF2 cells and animal models could be targeted and selectively died.

Results from this CTF Contract Award in 2013-14 were key to submitting and obtaining a larger Investigator-Initiated Research Award sponsored by the Neurofibromatosis Research Program (NFRP) at the Department of Defense (DoD) Congressionally Directed Medical Research Program (CDMRP).

Thanks to this new NFRP award, in 2014 Dr. Fernandez-Valle started a second phase of testing in her laboratory to evaluate multiple 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.  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.

As part of the CTF Synodos for NF2 Consortium, Dr. Fernandez-Valle is also collaborating with seven other institutions to continue exploring these targets and others that could be targeted for the development of much needed NF2 therapies.



CDMRP Research News HighlightsPotential Therapeutics for Neurofibromatosis Type 2-Associated Schwannoma Tumors

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 Fernández-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.

CDMRP grant:

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