Advocure Funds NF2 Research for 2012

Having raised $100,000 from Advocure’s 2011 Halloween Bash, the 2012 awards went to Dr. Brad Welling, formerly of Ohio State University (OSU), and Dr. Marco Giovannini, director of The Center for Neural Tumor Research at House Research Institute (HRI).

Both of these facilities and researchers are highly noted for their work with NF2 individuals. Full details of their projects as follows:

Dr. Marco Giovannini

Former Director of the Center for Neural Tumor Research at HRI will be starting a Study of RAD001 for Treatment of NF2-related Vestibular Schwannoma.The purpose of the study is to determine if RAD001 treatment will shrink or slow the growth of the vestibular schwannoma(s) in Neurofibromatosis 2 (NF2) patients. Secondary objectives include determining if RAD001 treatment will improve hearing ability in NF2 patients.Components of the Center for Neural Tumor Research that are currently being implemented or are in development include:

  • Preclinical NF2 drug testing
  • Clinical Trials for NF2
  • An integrated biospecimen bank and multidisciplinary database for NF2
  • Program and facility for genetic analysis of NF2-related tumors

Development of personalized treatments for NF2 patients

Dr. Brad Welling

OBJECTIVES: to develop a medical therapy for NF2 VS and meningiomas utilizing two novel small-molecule compounds, AR-12 and AR-42. As well as to screen a library of pure, structurally-defined natural compounds for potent growth inhibitory activity in schwannomas and meningiomas.

Aim 1: 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.

Aim 2: 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.

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