Traditional and systems biology based drug discovery for the rare tumor syndrome neurofibromatosis type 2

Robert Allaway, Steve P. Angus, Roberta L. Beauchamp, Jaishri O. Blakeley, Marga Bott, Sarah S. Burns, Annemarie Carlstedt, Long Sheng Chang, Xin Chen, D. Clapp, Patrick A. DeSouza, Serkan Erdin, Cristina Fernandez-Valle, Justin Guinney, James F. Gusella, Stephen J. Haggarty, Gary L. Johnson, Salvatore La Rosa, Helen Morrison, Alejandra M. Petrilli & 11 others Scott R. Plotkin, Abhishek Pratap, Vijaya Ramesh, Noah Sciaky, Anat Stemmer-Rachamimov, Tim J. Stuhlmiller, Michael E. Talkowski, D. Bradley Welling, Charles Yates, Jon S. Zawistowski, Wen Ning Zhao

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Neurofibromatosis 2 (NF2) is a rare tumor suppressor syndrome that manifests with multiple schwannomas and meningiomas. There are no effective drug therapies for these benign tumors and conventional therapies have limited efficacy. Various model systems have been created and several drug targets have been implicated in NF2-driven tumorigenesis based on known effects of the absence of merlin, the product of the NF2 gene. We tested priority compounds based on known biology with traditional dose-concentration studies in meningioma and schwann cell systems. Concurrently, we studied functional kinome and gene expression in these cells pre- and post-treatment to determine merlin deficient molecular phenotypes. Cell viability results showed that three agents (GSK2126458, Panobinostat, CUDC-907) had the greatest activity across schwannoma and meningioma cell systems, but merlin status did not significantly influence response. In vivo, drug effect was tumor specific with meningioma, but not schwannoma, showing response to GSK2126458 and Panobinostat. In culture, changes in both the transcriptome and kinome in response to treatment clustered predominantly based on tumor type. However, there were differences in both gene expression and functional kinome at baseline between meningioma and schwannoma cell systems that may form the basis for future selective therapies. This work has created an openly accessible resource (www.synapse.org/SynodosNF2) of fully characterized isogenic schwannoma and meningioma cell systems as well as a rich data source of kinome and transcriptome data from these assay systems before and after treatment that enables single and combination drug discovery based on molecular phenotype.

Original languageEnglish (US)
Article numbere0197350
JournalPLoS One
Volume13
Issue number6
DOIs
StatePublished - Jun 1 2018

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Neurofibromin 2
Neurofibromatosis 2
Systems Biology
Meningioma
Drug Discovery
Neurilemmoma
Tumors
Biological Sciences
drugs
neoplasms
Gene expression
transcriptome
Neoplasms
cells
Drug therapy
Transcriptome
phenotype
Schwann cells
gene expression
combination drug therapy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Allaway, R., Angus, S. P., Beauchamp, R. L., Blakeley, J. O., Bott, M., Burns, S. S., ... Zhao, W. N. (2018). Traditional and systems biology based drug discovery for the rare tumor syndrome neurofibromatosis type 2. PLoS One, 13(6), [e0197350]. https://doi.org/10.1371/journal.pone.0197350

Traditional and systems biology based drug discovery for the rare tumor syndrome neurofibromatosis type 2. / Allaway, Robert; Angus, Steve P.; Beauchamp, Roberta L.; Blakeley, Jaishri O.; Bott, Marga; Burns, Sarah S.; Carlstedt, Annemarie; Chang, Long Sheng; Chen, Xin; Clapp, D.; DeSouza, Patrick A.; Erdin, Serkan; Fernandez-Valle, Cristina; Guinney, Justin; Gusella, James F.; Haggarty, Stephen J.; Johnson, Gary L.; La Rosa, Salvatore; Morrison, Helen; Petrilli, Alejandra M.; Plotkin, Scott R.; Pratap, Abhishek; Ramesh, Vijaya; Sciaky, Noah; Stemmer-Rachamimov, Anat; Stuhlmiller, Tim J.; Talkowski, Michael E.; Welling, D. Bradley; Yates, Charles; Zawistowski, Jon S.; Zhao, Wen Ning.

In: PLoS One, Vol. 13, No. 6, e0197350, 01.06.2018.

Research output: Contribution to journalArticle

Allaway, R, Angus, SP, Beauchamp, RL, Blakeley, JO, Bott, M, Burns, SS, Carlstedt, A, Chang, LS, Chen, X, Clapp, D, DeSouza, PA, Erdin, S, Fernandez-Valle, C, Guinney, J, Gusella, JF, Haggarty, SJ, Johnson, GL, La Rosa, S, Morrison, H, Petrilli, AM, Plotkin, SR, Pratap, A, Ramesh, V, Sciaky, N, Stemmer-Rachamimov, A, Stuhlmiller, TJ, Talkowski, ME, Welling, DB, Yates, C, Zawistowski, JS & Zhao, WN 2018, 'Traditional and systems biology based drug discovery for the rare tumor syndrome neurofibromatosis type 2', PLoS One, vol. 13, no. 6, e0197350. https://doi.org/10.1371/journal.pone.0197350
Allaway, Robert ; Angus, Steve P. ; Beauchamp, Roberta L. ; Blakeley, Jaishri O. ; Bott, Marga ; Burns, Sarah S. ; Carlstedt, Annemarie ; Chang, Long Sheng ; Chen, Xin ; Clapp, D. ; DeSouza, Patrick A. ; Erdin, Serkan ; Fernandez-Valle, Cristina ; Guinney, Justin ; Gusella, James F. ; Haggarty, Stephen J. ; Johnson, Gary L. ; La Rosa, Salvatore ; Morrison, Helen ; Petrilli, Alejandra M. ; Plotkin, Scott R. ; Pratap, Abhishek ; Ramesh, Vijaya ; Sciaky, Noah ; Stemmer-Rachamimov, Anat ; Stuhlmiller, Tim J. ; Talkowski, Michael E. ; Welling, D. Bradley ; Yates, Charles ; Zawistowski, Jon S. ; Zhao, Wen Ning. / Traditional and systems biology based drug discovery for the rare tumor syndrome neurofibromatosis type 2. In: PLoS One. 2018 ; Vol. 13, No. 6.
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AU - Bott, Marga

AU - Burns, Sarah S.

AU - Carlstedt, Annemarie

AU - Chang, Long Sheng

AU - Chen, Xin

AU - Clapp, D.

AU - DeSouza, Patrick A.

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AU - Stemmer-Rachamimov, Anat

AU - Stuhlmiller, Tim J.

AU - Talkowski, Michael E.

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AU - Yates, Charles

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AU - Zhao, Wen Ning

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