Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomas

Abraham Jacob, Janet Oblinger, Matthew L. Bush, Victoria Brendel, Griffin Santarelli, Abhik R. Chaudhury, Samuel Kulp, Krista M D La Perle, Ching Shih Chen, Long Sheng Chang, D. Bradley Welling

Research output: Contribution to journalArticle

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Abstract

Objectives/Hypothesis: Recent studies indicate that vestibular schwannomas (VSs) rely on phosphatidylinositol 3-kinase/AKT activation to promote cell proliferation and survival; therefore, targeting AKT may provide new therapeutic options. We have previously shown that AR42, a novel histone deacetylase inhibitor, potently suppresses VS growth in vitro at doses correlating with AKT inactivation. The objectives of the current study were translational: 1) to examine the end biologic effects of AR42 on tumor growth in vivo, 2) to validate AKT as its in vivo molecular target, 3) to determine whether AR42 penetrates the blood-brain barrier (BBB), and 4) to study the pharmacotoxicity profile of AR42. Study Design: In vivo mouse studies. Methods: AR42 was dosed orally in murine schwannoma allografts and human VS xenografts. Magnetic resonance imaging was used to quantify changes in tumor volume, and intracellular molecular targets were analyzed using immunohistochemistry. BBB penetration was assayed, and both blood-chemistry measurements and histology studies were used to evaluate toxicity. Results: Growth of schwannoma implants was dramatically decreased by AR42 at doses correlating with AKT dephosphorylation, cell cycle arrest, and apoptosis. AR42 penetrated the BBB, and wild-type mice fed AR42 for 6 months behaved normally and gained weight appropriately. Blood-chemistry studies and organ histology performed after 3 and 6 months of AR42 treatment demonstrated no clinically significant abnormalities. Conclusions: AR42 suppresses schwannoma growth at doses correlating with AKT pathway inhibition. This orally bioavailable drug penetrates the BBB, is well tolerated, and represents a novel candidate for translation to human VS clinical trials.

Original languageEnglish (US)
Pages (from-to)174-189
Number of pages16
JournalLaryngoscope
Volume122
Issue number1
DOIs
StatePublished - Jan 2012

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Histone Deacetylase Inhibitors
Acoustic Neuroma
Blood-Brain Barrier
Neurilemmoma
Growth
Histology
Phosphatidylinositol 3-Kinase
Therapeutics
Cell Cycle Checkpoints
Tumor Burden
Heterografts
Allografts
Cell Survival
Immunohistochemistry
Magnetic Resonance Imaging
Cell Proliferation
Clinical Trials
Apoptosis
Weights and Measures
Pharmaceutical Preparations

Keywords

  • AKT
  • apoptosis
  • AR42
  • cell cycle arrest
  • histone deacetylase
  • histone deacetylase inhibitors
  • merlin
  • Neurofibromatosis type 2
  • vestibular schwannoma

ASJC Scopus subject areas

  • Otorhinolaryngology

Cite this

Jacob, A., Oblinger, J., Bush, M. L., Brendel, V., Santarelli, G., Chaudhury, A. R., ... Welling, D. B. (2012). Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomas. Laryngoscope, 122(1), 174-189. https://doi.org/10.1002/lary.22392

Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomas. / Jacob, Abraham; Oblinger, Janet; Bush, Matthew L.; Brendel, Victoria; Santarelli, Griffin; Chaudhury, Abhik R.; Kulp, Samuel; La Perle, Krista M D; Chen, Ching Shih; Chang, Long Sheng; Welling, D. Bradley.

In: Laryngoscope, Vol. 122, No. 1, 01.2012, p. 174-189.

Research output: Contribution to journalArticle

Jacob, A, Oblinger, J, Bush, ML, Brendel, V, Santarelli, G, Chaudhury, AR, Kulp, S, La Perle, KMD, Chen, CS, Chang, LS & Welling, DB 2012, 'Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomas', Laryngoscope, vol. 122, no. 1, pp. 174-189. https://doi.org/10.1002/lary.22392
Jacob, Abraham ; Oblinger, Janet ; Bush, Matthew L. ; Brendel, Victoria ; Santarelli, Griffin ; Chaudhury, Abhik R. ; Kulp, Samuel ; La Perle, Krista M D ; Chen, Ching Shih ; Chang, Long Sheng ; Welling, D. Bradley. / Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomas. In: Laryngoscope. 2012 ; Vol. 122, No. 1. pp. 174-189.
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abstract = "Objectives/Hypothesis: Recent studies indicate that vestibular schwannomas (VSs) rely on phosphatidylinositol 3-kinase/AKT activation to promote cell proliferation and survival; therefore, targeting AKT may provide new therapeutic options. We have previously shown that AR42, a novel histone deacetylase inhibitor, potently suppresses VS growth in vitro at doses correlating with AKT inactivation. The objectives of the current study were translational: 1) to examine the end biologic effects of AR42 on tumor growth in vivo, 2) to validate AKT as its in vivo molecular target, 3) to determine whether AR42 penetrates the blood-brain barrier (BBB), and 4) to study the pharmacotoxicity profile of AR42. Study Design: In vivo mouse studies. Methods: AR42 was dosed orally in murine schwannoma allografts and human VS xenografts. Magnetic resonance imaging was used to quantify changes in tumor volume, and intracellular molecular targets were analyzed using immunohistochemistry. BBB penetration was assayed, and both blood-chemistry measurements and histology studies were used to evaluate toxicity. Results: Growth of schwannoma implants was dramatically decreased by AR42 at doses correlating with AKT dephosphorylation, cell cycle arrest, and apoptosis. AR42 penetrated the BBB, and wild-type mice fed AR42 for 6 months behaved normally and gained weight appropriately. Blood-chemistry studies and organ histology performed after 3 and 6 months of AR42 treatment demonstrated no clinically significant abnormalities. Conclusions: AR42 suppresses schwannoma growth at doses correlating with AKT pathway inhibition. This orally bioavailable drug penetrates the BBB, is well tolerated, and represents a novel candidate for translation to human VS clinical trials.",
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