The below projects were partially funded by AdvocureNF2. 100% of all donations went directly to fund NF2 research. We are saddened to announce that as of July 31, 2016, AdvocureNF2 is no longer a charity and will not be able to further fund these projects. Please consider directing your donations to the researchers below if you wish to support research with the goal to find a cure for NF2!
Led By: Children’s Tumor Foundation (CTF.org)
Pharmacokinetic Studies for Drugs of Interest in Treatment of Neurofibromatosis Type 2
Led By: Dr. Cristina Fernadez-Vale
Natural Compound Silvestrol Study to Treat NF2-associated Tumors
Led By: Dr. Long-Sheng Chang
Immortalization of Human Schwannoma Cells Using Conditioned Cellullar Reprogramming Technology
Led By: Chungling Yi
Led By: Dr. Marco Giovannini
Potential Chemotherapeutic Agents for the Treatment of NF2-associated Schwannoma and Meningioma
Led By: D. Bradley Welling and Long-Sheng Chang
The Ohio State University and Nationwide Children’s Hospital
Please note, as Dr Welling has recently transferred to MGH (Mass General Hospital) Dr. Chang will be overseeing this study at OSU.
- To develop a medical therapy for NF2 VS and meningiomas utilizing two novel small-molecule compounds.
Aim 1: AR-12 and AR-42
To develop a medical therapy for vestibular schwannomas and meningiomas, we have established several cell culture and animals models for NF2-associated schwannomas and meningiomas. Using these models, we have identified two novel small-molecule compounds, AR-12 and AR-42, that potently inhibit the growth of schwannomas and meningiomas. In particular, we showed that AR-42 treatment decreased phosphorylated AKT and induced cell cycle arrest at G2/M and apoptosis in both cultured vestibular schwannoma and meningioma cells.
In mice treatment with AR-42 inhibited the growth of tumor Xenograft by as much as 90%, and AR-42-treated meningioma Xenograft showed minimal regrowth over time. These results suggest that AR-42 should be further evaluated as a potential treatment for NF2-associated tumors. We propose to investigate the mechanism underlying AR-42-mediated G2/M arrest in schwannoma and meningioma cells and to examine the effects of AR-42 treatment in normal Schwann and meningeal cells compared with their tumor counterparts. It is anticipated that a better understanding of AR-42 action should aid in the design of clinical trials for patients with vestibular schwannomas and meningiomas.
Update Aim 1, March 2014
Based on our promising preclinical findings, Dr. Welling has initiated a Phase I clinical trial for AR-42 in vestibular schwannomas and meningiomas. To date, five NF2 patients have been enrolled in the AR-42 clinical trial. Tumors in the participants were monitored by magnetic resonance imaging (MRI). Comparison of MRIs prior to and following treatment reveals that some tumors have shrunk in size or decreased in growth rate, while some others remain stable. Two of the patients underwent surgery to remove one of their vestibular schwannomas. We have performed morphoproteomic analysis to identify deregulated signaling molecules in these tumors. The information obtained has been used to better understand tumor growth behavior and to further inform future therapies for these patients.
- In addition to screen a library of pure, structurally-defined natural compounds for potent growth inhibitory activity in schwannomas and meningiomas.
Aim 2: Silvestrol
We have screened a library of pure, structurally-defined natural compounds for potent growth inhibitory activity in schwannomas and meningiomas. Natural products of microbe, plant, or marine origin, either in their naturally occurring or synthetically-modified forms, have played an important role as established cancer therapeutic agents.
Our preliminary screening has identified several potent compounds with IC50 in the submicromolar ornanomolar ranges. For example, silvestrol, a rocaglate derivative from tropical Asian plant Aglaia foveolata, showed an IC50 value of 4 and 10 nM in vestibular schwannoma and meningioma cells, respectively. Compared to 20 and 7 micromolar for curcumin (which is a compound extracted from the rhizome of a common spice turmeric) and was recently shown to possess some inhibitory activity in a viral oncogene-transformed vestibular schwannoma cell line.
We propose to continue screening the entire natural compound library for additional potent growth inhibitors of schwannoma and meningioma and to investigate the molecular pathways that are affected by these natural compounds, including silvestrol. Given that natural product compounds have substantial structural diversity and frequently afford new mechanisms of biological activity, some of the natural compounds that potently inhibit the growth of NF2-associated tumors may be used as potential therapeutic agents, ultimately leading to a cure for this devastating disease.
Update Aim 2, March 2014
Previously, we found that silvestrol potently inhibited the growth of Nf2-deficient schwannomas and silvestrol-treated tumors exhibited decreased cell density and increased cell death. Silvestrol induced cell-cycle arrest at G2/M in both schwannoma and meningioma cells. Consistently, silvestrol reduced the levels of several signaling molecules, including cyclins, phospho-AKT (p-AKT), p-ERKs, PAK1, and FAK. The mechanism by which silvestrol suppresses tumor growth is mediated, at least in part, through translation inhibition. Interestingly, we found that schwannoma cells express higher levels of eukaryotic translation initiation factor 4E (eIF-4E) than normal Schwann cells. Similarly, meningioma cells have more eIF4E expression than meningeal cells. We are in the process of preparing a manuscript to include all of these findings for publication.
In an effort to accelerate the translation of silvestrol to clinical evaluation, we previously tested ten silvestrol-related natural compounds and found five of them, including methyl rocaglate and methyl 4′-demethoxy-3′,4′-methylenedioxyrocaglate, with potent growth inhibitory activities in schwannoma and meningioma cells, similar to silvestrol. Importantly, these compounds have chemical structures similar to but simpler (smaller molecules) than silvestrol and, therefore, they will be easier to synthesize for clinical use. We are presently generating schwannoma-bearing mice and will use them to evaluate the antitumor activities of methyl rocaglate and methyl 4′-demethoxy-3′,4′-methylenedioxyrocaglate.