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Therapeutic potential of HSP90 inhibition for neurofibromatosis type 2

Therapeutic potential of HSP90 inhibition for neurofibromatosis type 2
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.

Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Female, HSP90 Heat-Shock Proteins, Humans, Lactones, Mice, Mice, Nude, Mice, Transgenic, Neurofibromatosis 2, Oximes, Proteolysis, Transcriptome, Xenograft Model Antitumor Assays, Journal Article, Research Support, Non-U.S. Gov't
1078-0432
3856-70
Tanaka, Karo
d923efab-ad3f-4aa8-9a41-5383427cb9cb
Eskin, Ascia
ddf1313d-c3ef-405e-a93b-79c011815d10
Chareyre, Fabrice
63e52a74-42af-4a37-98ee-0e8c786bb251
Jessen, Walter J
c6be7e01-58fc-4c37-8009-b59d2f5cede0
Manent, Jan
458a1a8a-f68d-4d4e-8d63-5ef41b071b6f
Niwa-Kawakita, Michiko
553a84a5-359b-47f3-8b31-9162cba5ee87
Chen, Ruihong
e360da12-21c1-42be-8e7e-d7ba7b641322
White, Cory H
45233a78-f0c9-4696-8aaf-1b2673f83c91
Vitte, Jeremie
588a94d7-03b7-4abb-b83a-b7e93fb65dae
Jaffer, Zahara M
f24baef8-17cb-415d-b7d8-5bee5e6916f7
Nelson, Stanley F
1b4c6150-e1de-4055-aa30-0baa0646c869
Rubenstein, Allan E
53166058-6d2c-4c42-bb5b-c9186e11f5fd
Giovannini, Marco
75029c55-dd99-4ad2-bb1a-4a40ea91e21f
Tanaka, Karo
d923efab-ad3f-4aa8-9a41-5383427cb9cb
Eskin, Ascia
ddf1313d-c3ef-405e-a93b-79c011815d10
Chareyre, Fabrice
63e52a74-42af-4a37-98ee-0e8c786bb251
Jessen, Walter J
c6be7e01-58fc-4c37-8009-b59d2f5cede0
Manent, Jan
458a1a8a-f68d-4d4e-8d63-5ef41b071b6f
Niwa-Kawakita, Michiko
553a84a5-359b-47f3-8b31-9162cba5ee87
Chen, Ruihong
e360da12-21c1-42be-8e7e-d7ba7b641322
White, Cory H
45233a78-f0c9-4696-8aaf-1b2673f83c91
Vitte, Jeremie
588a94d7-03b7-4abb-b83a-b7e93fb65dae
Jaffer, Zahara M
f24baef8-17cb-415d-b7d8-5bee5e6916f7
Nelson, Stanley F
1b4c6150-e1de-4055-aa30-0baa0646c869
Rubenstein, Allan E
53166058-6d2c-4c42-bb5b-c9186e11f5fd
Giovannini, Marco
75029c55-dd99-4ad2-bb1a-4a40ea91e21f

Tanaka, Karo, Eskin, Ascia, Chareyre, Fabrice, Jessen, Walter J, Manent, Jan, Niwa-Kawakita, Michiko, Chen, Ruihong, White, Cory H, Vitte, Jeremie, Jaffer, Zahara M, Nelson, Stanley F, Rubenstein, Allan E and Giovannini, Marco (2013) Therapeutic potential of HSP90 inhibition for neurofibromatosis type 2. Clinical Cancer Research, 19 (14), 3856-70. (doi:10.1158/1078-0432.CCR-12-3167).

Record type: Article

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.

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More information

Published date: 15 July 2013
Keywords: Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Female, HSP90 Heat-Shock Proteins, Humans, Lactones, Mice, Mice, Nude, Mice, Transgenic, Neurofibromatosis 2, Oximes, Proteolysis, Transcriptome, Xenograft Model Antitumor Assays, Journal Article, Research Support, Non-U.S. Gov't
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 409392
URI: http://eprints.soton.ac.uk/id/eprint/409392
ISSN: 1078-0432
PURE UUID: 3c8a9b4b-c909-4f5e-af2b-57509f22b272

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Date deposited: 28 May 2017 04:08
Last modified: 02 Sep 2022 17:13

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Contributors

Author: Karo Tanaka
Author: Ascia Eskin
Author: Fabrice Chareyre
Author: Walter J Jessen
Author: Jan Manent
Author: Michiko Niwa-Kawakita
Author: Ruihong Chen
Author: Cory H White
Author: Jeremie Vitte
Author: Zahara M Jaffer
Author: Stanley F Nelson
Author: Allan E Rubenstein
Author: Marco Giovannini

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