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The Foundation's recent initiatives to accelerate the identification of NF drug therapies have included a Clinical Trial Awards program to fund small scale clinical trials. Through that program, last year we were delighted to announce the funding of two trials: lapatinib for NF2 vestibular schwannoma, with $125,000 awarded to Dr. Jaishri Blakeley at Johns Hopkins University in collaboration with GlaxoSmithKline; and sorafenib for NF1 plexiform neurofibroma, with $125,000 awarded to Dr. Bruce Korf
at the University of Alabama to expand on a National Cancer Institute trial headed by Dr. Brigitte Widemann and Dr. Aerang Kim of NCI.

In fall 2010, responding to inquiries from the research and clinical communities we expanded the scope of this program to Clinical Research Awards. These can still be used to fund small scale clinical trials, but can also be used for adjunct clinical studies to identify ‘biomarkers’. Biomarkers are clinical indicators that can be used to determine if NF is progressing or if a drug is working to slow progression. Biomarkers will ultimately be used to improve the design and implementation of clinical trials making them faster and more meaningful.

Four Clinical Research Awards have been funded: one clinical trial, and three adjunct biomarker studies. These are described below. Following an enthusiastic response to this program, CTF hopes to announce the next deadline for Clinical Research Award applications in spring 2011.

Phase II Trial of Rapamycin – NF2 Tumors
Matthias Karajannis, New York University Langone Medical Center
Industry Collaborator: Novartis

In the past couple of years, clinical trials for candidate NF2 drugs have commenced, driven in part by CTF’s commitment to advancing this area through hosting expert consensus advisory meetings, and also by funding some of the first NF2 clinical trials. This is the second NF2 clinical trial that CTF has funded; the first, a Phase Zero (presurgery) trial of lapatinib, is near conclusion and has been a collaboration between Dr. Jaishri Blakeley (Johns Hopkins University -- pictured on the right) and Dr. Matthias Karajannis (New York University Langone Medical Center). In this newly funded NF2 clinical trial, RAD001 (rapamycin) is assessed as a candidate drug therapy for NF2 by its effects on the growth and/or shrinkage of the characteristic NF2 tumors vestibular schwannoma, meningioma and ependymoma. RAD001 has been widely tested in patients and is known to be safe; indeed it was one of the first drugs to enter large scale clinical trials for NF1 plexiform tumors. This trial asks whether there is any potential efficacy of RAD001 in NF2. If there are promising results, this trial will pave the way for future combination therapy drug trials, since animal studies have suggested that RAD001 might be additive if combined with other drugs such as Bevacizumab or Laptinib, also being tested as candidate NF2 drug therapies.

Novartis is providing the drug and additional support for this trial, leveraging CTF’s investment.

The following three studies, while independent of one another, are all being done as adjunct studies to the Congressionally Directed Medical Research Program’s Phase II Clinical Trials Consortium. By funding studies in conjunction with larger government or industry funded studies, the Foundation maximizes the support of our donors.

New Metrics for Optic Pathway Glioma Trials
Rob Avery, Children’s National Medical Center

As NF clinical trials move ahead, it is becoming apparent that there is a need to develop more sensitive approaches for determining as early as possible if a drug is effective. This will mean that the timeline of clinical trials can be shortened, and that a greater number of patients can benefit more rapidly from promising drugs. In this
study, Dr. Avery is utilizing a new technology termed Spectral Domain Optical Coherence Tomography that can be used to detect changes in the optic pathway that will predict as early as possible whether trials to assess drugs for NF1-related optic pathway glioma are looking promising or not. By establishing a reliable quantitative biomarker, the results of this study will make a significant contribution to the advancement of drug treatment for NF1 optic pathway glioma. It should also improve ongoing ophthalmologic care for children with NF1 by acquiring much needed knowledge about the pathophysiology and natural history of NF1-related optic pathway gliomas. This new technology will be an essential biomarker component of future optic pathway glioma therapeutic clinical trials.

Blood Predictors of NF1 Severity
Cynthia Hingtgen, Indiana University

Vascular disease is a manifestation of NF1 that is frequently overlooked, but individuals with NF1, particularly younger patients, are at a significantly elevated risk of vascular disease. Researchers are learning progressively more about the genetics and molecular signaling events that underlie this manifestation. This study aims to take this learning a step further and develop diagnostics to determine how severe vascular disease is likely to be by identifying a blood-borne marker that is
elevated in high-risk patients. Dr. Hingtgenelevated in high-risk patients. Dr. Hingtgen will analyze specific subsets of inflammatory cells that are present in the blood to test if they serve as diagnostic biomarkers of both the incidence and severity of vascular disease in NF1 patients. The study will include clinical analysis as well as animal model studies of NF1 vasculopathy. Based on the findings, Dr. Hingtgen and colleagues anticipate submitting within the next 18 months an application for a clinical trial focused on new approaches for treating NF1 vascular disease.

Computerized ‘maze’ for NF1 Learning Disabilities Trials
Nicole Ullrich, Children’s Hospital Boston
Significant progress has been made in the past ten years in understanding, and developing clinical management approaches, for learning disabilities that affect an estimated two-thirds of persons with NF1. Groundbreaking research emerged from studies on genetic mouse models with NF1 related learning disabilities. When these mice were given the drug Lovastatin, they showed improved learning in the Morris Water Maze, physical test which involves the mouse swimming and locating a rest platform in the water. Lovastatin is now in NF1 clinical trials, and clinicians are trying to develop optimized tests to monitor the effects of the drugs on learning. In this vein, this study has developed a computerized equivalent of the Morris Water Maze that children can navigate virtually from the armchair, and which will allow assessment of learning improvements before and after treatment with Lovastatin. If successful, this testing approach could become a cornerstone of future NF1 learning disabilities trials.