Allan E. Rubenstein

Consensus Recommendations to Accelerate Clinical Trials for Neurofibromatosis Type 2

Purpose: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder associated primarily with bilateral schwannomas seen on the superior vestibular branches of the eighth cranial nerves. Significant morbidity can result from surgical treatment of these tumors. Meningiomas, ependymomas, and other benign central nervous system tumors are also common in NF2. The lack of effective treatments for NF2 marks an unmet medical need. Experimental Design: Here, we provide recommendations from a workshop, cochaired by Drs. D. Gareth Evans and Marco Giovannini, of 36 international researchers, physicians, representatives of the biotechnology industry, and patient advocates on how to accelerate progress toward NF2 clinical trials. Results: Workshop participants reached a consensus that, based on current knowledge, the time is right to plan and implement NF2 clinical trials. Obstacles impeding NF2 clinical trials and how to address them were discussed, as well as the candidate therapeutic pipeline for NF2. Conclusions: Both phase 0 and phase II NF2 trials are near-term options for NF2 clinical trials. The number of NF2 patients in the population remains limited, and successful recruitment will require ongoing collaboration efforts between NF2 clinics. (Clin Cancer Res 2009;15(16):5032–9)

Neurofibromatosis. A review of the clinical problem.

NF is a relatively common genetic disorder which predisposes to a variety of clinical manifestations involving multiple body systems. NF poses important questions to researchers involved with developmental neurobiology, nerve regeneration and growth, the mechanism of malignant degeneration, and the use of molecular techniques to identify genetic disorders. It is hoped that this conference will bring together researchers who have developed new techniques in these areas and will encourage them to apply these techniques to the problem of NF.

Neurofibromatosis: A Handbook for Patients, Families, and Health Care Professionals

Preface 1. Introduction and History 2. The Many Faces of NF 3. The Pathogenesis of NF1 and NF2 4. Genetics and Genetic Counseling in NF1 and NF2 5. Diagnosis and Overall Management of NF1 6. Neurofibromas and Malignant Peripheral Nerve Sheath Tumors in NF1 7. Other Neural Tumors and Nervous System Abnormalities in NF1 8. Cognitive Function and Learning Disabilities in NF1 9. Other Features of NF1 10. Diagnosis and Overall Management of NF2 11. Management of Particular NF2 Features 12. Schwannomatosis 13. Psychosocial Impact of Neurofibromatosis 14. Practical and Quality-of-Life Issues 15. Research About Neurofibromatosis Glossary Appendix: The National Neurofibromatosis Foundation, Inc. Index

Therapeutic Potential of HSP90 Inhibition for Neurofibromatosis type 2

Purpose: The growth and survival of neurofibromatosis type 2 (NF2)–deficient cells are enhanced by the activation of multiple signaling pathways including ErbBs/IGF-1R/Met, PI3K/Akt, and Ras/Raf/Mek/Erk1/2. The chaperone protein HSP90 is essential for the stabilization of these signaling molecules. The aim of the study was to characterize the effect of HSP90 inhibition in various NF2-deficient models. Experimental Design: We tested efficacy of the small-molecule NXD30001, which has been shown to be a potent HSP90 inhibitor. The antiproliferative activity of NXD30001 was tested in NF2-deficient cell lines and in human primary schwannoma and meningioma cultures in vitro. The antitumor efficacy of HSP90 inhibition in vivo was verified in two allograft models and in one NF2 transgenic model. The underlying molecular alteration was further characterized by a global transcriptome approach. Results: NXD30001 induced degradation of client proteins in and suppressed proliferation of NF2-deficient cells. Differential expression analysis identified subsets of genes implicated in cell proliferation, cell survival, vascularization, and Schwann cell differentiation whose expression was altered by NXD30001 treatment. The results showed that NXD30001 in NF2-deficient schwannoma suppressed multiple pathways necessary for tumorigenesis. Conclusions: HSP90 inhibition showing significant antitumor activity against NF2-related tumor cells in vitro and in vivo represents a promising option for novel NF2 therapies. Clin Cancer Res; 19(14); 3856–70. ©2013 AACR.

Advances in neurofibromatosis 2 (NF2): a workshop report.

DAVID J. LIM*, ALLAN E. RUBENSTEIN, D. GARETH EVANS, TYLER JACKS, BERND G. SEIZINGER, MICHAEL E. BASER, DAVID BEEBE, DERALD E. BRACKMANN, E. ANTONIO CHIOCCA, RICHARD G. FEHON, MARC0 GIOVANNINI, ROBERT GLAZER, JAMES F. GUSELLA, DAVID H. GUTMANN, BRUCE KORF, FRANK LIEBERMAN, ROBERT MARTUZA, ANDREA I. McCLATCHEY, DILYS M. PARRY, STEFAN M. PULST, VIJAYA RAMESH, W. JAY RAMSEY, NANCY RATNER, J. LYNN RUTKOWSKI, MARTIN RUTTLEDGE and DAVID E. WEINSTEIN