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.

Temporal Phosphoproteome Dynamics Induced by an ATP Synthase Inhibitor Citreoviridin*

“…Moreover, a significant decrease in HSP90AB1 phosphorylation was found not only in cultured cells but also in the xenograft phosphoproteome, indicating its crucial role in citreoviridin treatment. It has been reported that cells treated with HSP90 inhibitor showed reduced activity in signaling pathways, including Akt and MAPK/ERK cascades (63,64,67). Our study showed that the phosphorylation level of one key component involved in MAPK/ERK signaling, MAPK1, was markedly diminished at late stages in citreoviridin-stimulated responses.…”

A novel small molecule HSP90 inhibitor, NXD30001, differentially induces heat shock proteins in nervous tissue in culture and in vivo

“…In plasma, NXD30001 cleared quickly and reached near the lower limit of quantitation level at 6 h. In contrast, NXD30001 levels in brain, spinal cord, liver, and muscle were still above the neuroprotective concentration used in culture (40 nM, equivalent to 20 ng/g of tissue) at 6 h, despite substantial decrease from levels at 1 h. Drug levels in liver and muscle were much higher than those in nervous tissues. To convert ng/g to molar concentration, multiply by 0.5 turnover of cell signaling molecules that are HSP90 client proteins (Barluenga et al 2008Wang et al 2009;Zhu et al 2010;Tanaka et al 2013).…”

Update from the 2013 international neurofibromatosis conference

“…The antiproliferative activity of NXD30001 was tested in NF2-deficient cell lines and in human primary schwannoma and meningioma cultures in vitro, and in two allograft models and in one Nf2 transgenic model in vivo [Tanaka et al, 2013]. They found that NXD30001 induced degradation of client proteins and suppressed proliferation of NF2-deficient cells.…”