Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomas
- 22 November 2011
- journal article
- research article
- Published by Wiley in The Laryngoscope
- Vol. 122 (1), 174-189
- https://doi.org/10.1002/lary.22392
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.Keywords
This publication has 104 references indexed in Scilit:
- AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomasNeuro-Oncology, 2011
- ErbB/HER receptor activation and preclinical efficacy of lapatinib in vestibular schwannomaNeuro-Oncology, 2010
- Growth inhibitory and anti-tumour activities of OSU-03012, a novel PDK-1 inhibitor, on vestibular schwannoma and malignant schwannoma cellsEuropean Journal of Cancer, 2009
- Merlin and the ERM proteins – regulators of receptor distribution and signaling at the cell cortexTrends in Cell Biology, 2009
- Phosphatidylinositol 3-Kinase/AKT Pathway Activation in Human Vestibular SchwannomaOtology & Neurotology, 2008
- Nf2/Merlin: a coordinator of receptor signalling and intercellular contactBritish Journal of Cancer, 2007
- Contact-dependent inhibition of EGFR signaling by Nf2/MerlinThe Journal of cell biology, 2007
- Intrinsic apoptotic and thioredoxin pathways in human prostate cancer cell response to histone deacetylase inhibitorProceedings of the National Academy of Sciences of the United States of America, 2006
- Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancerNature Reviews Cancer, 2006
- Perturbations of the AKT signaling pathway in human cancerOncogene, 2005