TY - JOUR
T1 - Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomas
AU - Jacob, Abraham
AU - Oblinger, Janet
AU - Bush, Matthew L.
AU - Brendel, Victoria
AU - Santarelli, Griffin
AU - Chaudhury, Abhik R.
AU - Kulp, Samuel
AU - La Perle, Krista M.D.
AU - Chen, Ching Shih
AU - Chang, Long Sheng
AU - Welling, D. Bradley
PY - 2012/1
Y1 - 2012/1
N2 - 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.
AB - 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.
KW - AKT
KW - AR42
KW - Neurofibromatosis type 2
KW - apoptosis
KW - cell cycle arrest
KW - histone deacetylase
KW - histone deacetylase inhibitors
KW - merlin
KW - vestibular schwannoma
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U2 - 10.1002/lary.22392
DO - 10.1002/lary.22392
M3 - Article
C2 - 22109824
AN - SCOPUS:84355161485
SN - 0023-852X
VL - 122
SP - 174
EP - 189
JO - Laryngoscope
JF - Laryngoscope
IS - 1
ER -