AustralieFrV1, Pmc, Corpus, bibRecord, 002178

Therapeutic Potential of HSP90 Inhibition for Neurofibromatosis Type 2

Identifieur interne : 002178 ( Pmc/Corpus ); précédent : 002177; suivant : 002179

Therapeutic Potential of HSP90 Inhibition for Neurofibromatosis Type 2

Auteurs : 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

Source :

Clinical cancer research : an official journal of the American Association for Cancer Research [ 1078-0432 ] ; 2013.

RBID : PMC:4331126

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.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331126

DOI: 10.1158/1078-0432.CCR-12-3167
PubMed: 23714726
PubMed Central: 4331126

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PMC:4331126

Le document en format XML

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<author><name sortKey="Tanaka, Karo" sort="Tanaka, Karo" uniqKey="Tanaka K" first="Karo" last="Tanaka">Karo Tanaka</name>
<affiliation><nlm:aff id="A1">Center for Neural Tumor Research, House Research Institute</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Eskin, Ascia" sort="Eskin, Ascia" uniqKey="Eskin A" first="Ascia" last="Eskin">Ascia Eskin</name>
<affiliation><nlm:aff id="A3">Department of Human Genetics, University of California, Los Angeles</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chareyre, Fabrice" sort="Chareyre, Fabrice" uniqKey="Chareyre F" first="Fabrice" last="Chareyre">Fabrice Chareyre</name>
<affiliation><nlm:aff id="A1">Center for Neural Tumor Research, House Research Institute</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jessen, Walter J" sort="Jessen, Walter J" uniqKey="Jessen W" first="Walter J." last="Jessen">Walter J. Jessen</name>
<affiliation><nlm:aff id="A6">Informatics, Covance Inc., Princeton, New Jersey</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Manent, Jan" sort="Manent, Jan" uniqKey="Manent J" first="Jan" last="Manent">Jan Manent</name>
<affiliation><nlm:aff id="A7">Peter MacCallum Cancer Institute, Melbourne, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Niwa Kawakita, Michiko" sort="Niwa Kawakita, Michiko" uniqKey="Niwa Kawakita M" first="Michiko" last="Niwa-Kawakita">Michiko Niwa-Kawakita</name>
<affiliation><nlm:aff id="A8">Inserm U944, CNRS U7212, Université Paris Diderot-Paris 7, Institut Universitaire d'Hématologie, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chen, Ruihong" sort="Chen, Ruihong" uniqKey="Chen R" first="Ruihong" last="Chen">Ruihong Chen</name>
<affiliation><nlm:aff id="A5">NexGenix Pharmaceuticals, Burlingame, California</nlm:aff>
</affiliation>
</author>
<author><name sortKey="White, Cory H" sort="White, Cory H" uniqKey="White C" first="Cory H." last="White">Cory H. White</name>
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</affiliation>
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<author><name sortKey="Vitte, Jeremie" sort="Vitte, Jeremie" uniqKey="Vitte J" first="Jeremie" last="Vitte">Jeremie Vitte</name>
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</affiliation>
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<author><name sortKey="Jaffer, Zahara M" sort="Jaffer, Zahara M" uniqKey="Jaffer Z" first="Zahara M." last="Jaffer">Zahara M. Jaffer</name>
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</affiliation>
</author>
<author><name sortKey="Nelson, Stanley F" sort="Nelson, Stanley F" uniqKey="Nelson S" first="Stanley F." last="Nelson">Stanley F. Nelson</name>
<affiliation><nlm:aff id="A3">Department of Human Genetics, University of California, Los Angeles</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rubenstein, Allan E" sort="Rubenstein, Allan E" uniqKey="Rubenstein A" first="Allan E." last="Rubenstein">Allan E. Rubenstein</name>
<affiliation><nlm:aff id="A9">New York University Langone Medical Center, New York, New York</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Giovannini, Marco" sort="Giovannini, Marco" uniqKey="Giovannini M" first="Marco" last="Giovannini">Marco Giovannini</name>
<affiliation><nlm:aff id="A1">Center for Neural Tumor Research, House Research Institute</nlm:aff>
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<affiliation><nlm:aff id="A4">Department of Cell and Neurobiology, University of Southern California, Keck School of Medicine, Los Angeles</nlm:aff>
</affiliation>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Therapeutic Potential of HSP90 Inhibition for Neurofibromatosis Type 2</title>
<author><name sortKey="Tanaka, Karo" sort="Tanaka, Karo" uniqKey="Tanaka K" first="Karo" last="Tanaka">Karo Tanaka</name>
<affiliation><nlm:aff id="A1">Center for Neural Tumor Research, House Research Institute</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Eskin, Ascia" sort="Eskin, Ascia" uniqKey="Eskin A" first="Ascia" last="Eskin">Ascia Eskin</name>
<affiliation><nlm:aff id="A3">Department of Human Genetics, University of California, Los Angeles</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chareyre, Fabrice" sort="Chareyre, Fabrice" uniqKey="Chareyre F" first="Fabrice" last="Chareyre">Fabrice Chareyre</name>
<affiliation><nlm:aff id="A1">Center for Neural Tumor Research, House Research Institute</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jessen, Walter J" sort="Jessen, Walter J" uniqKey="Jessen W" first="Walter J." last="Jessen">Walter J. Jessen</name>
<affiliation><nlm:aff id="A6">Informatics, Covance Inc., Princeton, New Jersey</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Manent, Jan" sort="Manent, Jan" uniqKey="Manent J" first="Jan" last="Manent">Jan Manent</name>
<affiliation><nlm:aff id="A7">Peter MacCallum Cancer Institute, Melbourne, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Niwa Kawakita, Michiko" sort="Niwa Kawakita, Michiko" uniqKey="Niwa Kawakita M" first="Michiko" last="Niwa-Kawakita">Michiko Niwa-Kawakita</name>
<affiliation><nlm:aff id="A8">Inserm U944, CNRS U7212, Université Paris Diderot-Paris 7, Institut Universitaire d'Hématologie, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chen, Ruihong" sort="Chen, Ruihong" uniqKey="Chen R" first="Ruihong" last="Chen">Ruihong Chen</name>
<affiliation><nlm:aff id="A5">NexGenix Pharmaceuticals, Burlingame, California</nlm:aff>
</affiliation>
</author>
<author><name sortKey="White, Cory H" sort="White, Cory H" uniqKey="White C" first="Cory H." last="White">Cory H. White</name>
<affiliation><nlm:aff id="A2">Section on Genetics of Hereditary Ear Disorders, House Research Institute</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Vitte, Jeremie" sort="Vitte, Jeremie" uniqKey="Vitte J" first="Jeremie" last="Vitte">Jeremie Vitte</name>
<affiliation><nlm:aff id="A1">Center for Neural Tumor Research, House Research Institute</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jaffer, Zahara M" sort="Jaffer, Zahara M" uniqKey="Jaffer Z" first="Zahara M." last="Jaffer">Zahara M. Jaffer</name>
<affiliation><nlm:aff id="A1">Center for Neural Tumor Research, House Research Institute</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nelson, Stanley F" sort="Nelson, Stanley F" uniqKey="Nelson S" first="Stanley F." last="Nelson">Stanley F. Nelson</name>
<affiliation><nlm:aff id="A3">Department of Human Genetics, University of California, Los Angeles</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rubenstein, Allan E" sort="Rubenstein, Allan E" uniqKey="Rubenstein A" first="Allan E." last="Rubenstein">Allan E. Rubenstein</name>
<affiliation><nlm:aff id="A9">New York University Langone Medical Center, New York, New York</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Giovannini, Marco" sort="Giovannini, Marco" uniqKey="Giovannini M" first="Marco" last="Giovannini">Marco Giovannini</name>
<affiliation><nlm:aff id="A1">Center for Neural Tumor Research, House Research Institute</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A4">Department of Cell and Neurobiology, University of Southern California, Keck School of Medicine, Los Angeles</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Clinical cancer research : an official journal of the American Association for Cancer Research</title>
<idno type="ISSN">1078-0432</idno>
<imprint><date when="2013">2013</date>
</imprint>
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<front><div type="abstract" xml:lang="en"><sec id="S1"><title>Purpose</title>
<p id="P1">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.</p>
</sec>
<sec id="S2"><title>Experimental Design</title>
<p id="P2">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 <italic>in vitro</italic>
. The antitumor efficacy of HSP90 inhibition <italic>in vivo</italic>
 was verified in two allograft models and in one NF2 transgenic model. The underlying molecular alteration was further characterized by a global transcriptome approach.</p>
</sec>
<sec id="S3"><title>Results</title>
<p id="P3">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.</p>
</sec>
<sec id="S4"><title>Conclusions</title>
<p id="P4">HSP90 inhibition showing significant antitumor activity against NF2-related tumor cells <italic>in vitro</italic>
 and <italic>in vivo</italic>
 represents a promising option for novel NF2 therapies.</p>
</sec>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
  <pmc-dir>properties manuscript</pmc-dir>
  <front><journal-meta><journal-id journal-id-type="nlm-journal-id">9502500</journal-id>
<journal-id journal-id-type="pubmed-jr-id">8794</journal-id>
<journal-id journal-id-type="nlm-ta">Clin Cancer Res</journal-id>
<journal-id journal-id-type="iso-abbrev">Clin. Cancer Res.</journal-id>
<journal-title-group><journal-title>Clinical cancer research : an official journal of the American Association for Cancer Research</journal-title>
</journal-title-group>
<issn pub-type="ppub">1078-0432</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">23714726</article-id>
<article-id pub-id-type="pmc">4331126</article-id>
<article-id pub-id-type="doi">10.1158/1078-0432.CCR-12-3167</article-id>
<article-id pub-id-type="manuscript">NIHMS658790</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Therapeutic Potential of HSP90 Inhibition for Neurofibromatosis Type 2</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Tanaka</surname>
<given-names>Karo</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Eskin</surname>
<given-names>Ascia</given-names>
</name>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chareyre</surname>
<given-names>Fabrice</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jessen</surname>
<given-names>Walter J.</given-names>
</name>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Manent</surname>
<given-names>Jan</given-names>
</name>
<xref ref-type="aff" rid="A7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Niwa-Kawakita</surname>
<given-names>Michiko</given-names>
</name>
<xref ref-type="aff" rid="A8">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chen</surname>
<given-names>Ruihong</given-names>
</name>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>White</surname>
<given-names>Cory H.</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vitte</surname>
<given-names>Jeremie</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jaffer</surname>
<given-names>Zahara M.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nelson</surname>
<given-names>Stanley F.</given-names>
</name>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rubenstein</surname>
<given-names>Allan E.</given-names>
</name>
<xref ref-type="aff" rid="A9">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Giovannini</surname>
<given-names>Marco</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Center for Neural Tumor Research, House Research Institute</aff>
<aff id="A2"><label>2</label>
Section on Genetics of Hereditary Ear Disorders, House Research Institute</aff>
<aff id="A3"><label>3</label>
Department of Human Genetics, University of California, Los Angeles</aff>
<aff id="A4"><label>4</label>
Department of Cell and Neurobiology, University of Southern California, Keck School of Medicine, Los Angeles</aff>
<aff id="A5"><label>5</label>
NexGenix Pharmaceuticals, Burlingame, California</aff>
<aff id="A6"><label>6</label>
Informatics, Covance Inc., Princeton, New Jersey</aff>
<aff id="A7"><label>7</label>
Peter MacCallum Cancer Institute, Melbourne, Australia</aff>
<aff id="A8"><label>8</label>
Inserm U944, CNRS U7212, Université Paris Diderot-Paris 7, Institut Universitaire d'Hématologie, Paris, France</aff>
<aff id="A9"><label>9</label>
New York University Langone Medical Center, New York, New York</aff>
<author-notes><corresp id="FN1">Corresponding Author: Marco Giovannini, House Research Institute, Center for Neural Tumor Research, 2100 West 3rd Street, Los Angeles, CA 90057. Phone: 213-989-6708; Fax: 213-989-6778; <email>mgiovannini@hei.org</email>
</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>8</day>
<month>2</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="epub"><day>28</day>
<month>5</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="ppub"><day>15</day>
<month>7</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>17</day>
<month>2</month>
<year>2015</year>
</pub-date>
<volume>19</volume>
<issue>14</issue>
<fpage>3856</fpage>
<lpage>3870</lpage>
<pmc-comment>elocation-id from pubmed: 10.1158/1078-0432.CCR-12-3167</pmc-comment>
      <permissions><copyright-statement>©2013 American Association for Cancer Research.</copyright-statement>
<copyright-year>2013</copyright-year>
</permissions>
<abstract><sec id="S1"><title>Purpose</title>
<p id="P1">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.</p>
</sec>
<sec id="S2"><title>Experimental Design</title>
<p id="P2">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 <italic>in vitro</italic>
. The antitumor efficacy of HSP90 inhibition <italic>in vivo</italic>
 was verified in two allograft models and in one NF2 transgenic model. The underlying molecular alteration was further characterized by a global transcriptome approach.</p>
</sec>
<sec id="S3"><title>Results</title>
<p id="P3">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.</p>
</sec>
<sec id="S4"><title>Conclusions</title>
<p id="P4">HSP90 inhibition showing significant antitumor activity against NF2-related tumor cells <italic>in vitro</italic>
 and <italic>in vivo</italic>
 represents a promising option for novel NF2 therapies.</p>
</sec>
</abstract>
</article-meta>
</front>
</pmc>
</record>

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Therapeutic Potential of HSP90 Inhibition for Neurofibromatosis Type 2

Therapeutic Potential of HSP90 Inhibition for Neurofibromatosis Type 2

Source :

Abstract

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