Therapeutic potential of HSP90 inhibition for neurofibromatosis type 2.

Abstract

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.

• Authors: Karo Tanaka, Ascia Eskin, Fabrice Chareyre, Walter J Jessen, Jan Manent, Michiko Niwa-Kawakita, Ruihong Chen, Cory H White, Jeremie Vitte, Zahara M Jaffer, Stanley F Nelson, Allan E Rubenstein, Marco Giovannini
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 14 Pg. 3856-70 (Jul 15 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23714726 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• HSP90 Heat-Shock Proteins
• HSP90AA1 protein, human
• HSP90AB1 protein, human
• Lactones
• Oximes
• pochoxime A

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Proliferation
• Female
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Lactones (pharmacology)
• Mice
• Mice, Nude
• Mice, Transgenic
• Neurofibromatosis 2 (drug therapy, metabolism)
• Oximes (pharmacology)
• Proteolysis
• Transcriptome (drug effects)
• Xenograft Model Antitumor Assays