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

Abstract

Objective/Hypothesis Recent studies indicate that vestibular schwannomas (VS) rely on PI3-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 AR42’s pharmacotoxicity profile. Study Design In vivo mouse studies Methods AR42 was dosed orally in murine schwannoma allografts and human vestibular schwannoma xenografts. MRI was used to quantify changes in tumor volume while intracellular molecular targets were analyzed using immunohistochemistry. Blood-brain barrier (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.

A unique histone deacetylase inhibitor alters microRNA expression and signal transduction in chemoresistant ovarian cancer cells

“…6 Additionally, while we did not examine Akt signaling in the current study, others have demonstrated that Akt signal inhibition (by AR42 and other agents) sensitized CP70 and other p53-dysfunctional, drug-resistant, ovarian cancer cells. 37,56 As AR42 has also been demonstrated to downregulate Akt activity, [7][8][9]12 blockade of that oncogenic signal pathway might represent another HDACI mechanism of resensitization of chemoresistant ovarian cancer cells (an antineoplastic effect we previously observed). 6 Similar to EMT, gene set enrichment analysis 35 also demonstrated AR42 gene expression profiles to negatively associate transition (EMT) (Fig.…”

“…Preclinical studies by our group and others have similarly shown potential therapeutic efficacy of a "rationally designed" HDACI, AR42 (formerly OSU-HDAC42, Arno Therapeutics), 5 against multiple myeloma, adult T-cell lymphomas and solid tumors of the ovary, liver and prostate, both singly or combined with other agents. [6][7][8][9][10][11][12] Various molecular mechanisms/processes have now been advanced to explain HDACI cancer cell-specific cytotoxicity (and non-toxicity toward normal cells), including upregulation of pro-apoptotic genes, downregulation of anti-apoptotic genes, abrogation of cell cycle checkpoints and increased production of reactive oxygen species (concurrent with diminished antioxidative response). 2,4 With some exceptions, however, many of those previously identified anticancer mechanisms were based on limited numbers of HDACI-altered genes, absent rigorous assessments of HDACI cumulative effects on signal pathways/ networks.…”

Efficacy of Combined Histone Deacetylase and Checkpoint Kinase Inhibition in a Preclinical Model of Human Burkitt Lymphoma

“…The combination prior to the start of any experiment. Three days after whole body irradiation (400 rads), 5 × 10 6 Raji cells in 100 μL PBS were implanted subcutaneously in the flank to establish tumors. After tumors reached >300 mm 3 , mice were randomly assigned to one of four treatment groups (7 animals/group): control (vehicle only), CHEK2i (1.0 mg/kg/dose), AR42 (10 mg/kg/dose), or combination of CHEK2i (1.0 mg/kg/dose) and AR42 (1.0 mg/kg/dose).…”

“…Currently, three such drugs are FDA-approved for the treatment of NHL (vorinostat, belinostat and romidepsin); a number of others are in clinical development for various hematologic malignancies (17,18). AR42, a phenylbutyrate-derived pan-HDACI, has been shown to have cytotoxic activity in several malignancies (4)(5)(6)(7)9,19,20). More recently, AR42 and other HDACIs have been reported to synergistically increase the cytotoxic activity of the α-CD22 monoclonal antibody (mAb) HB22.7 (14) and the α-CD20 mAb rituximab (11-13) on NHL cells.…”

“…Histone deacetylases mediate chromatin remodeling by removing acetyl groups from lysine residues in the core histones, which results in a more compact, transcriptionally repressed chromatin. Histone deacetylase inhibitors ( HDACIs) have been shown to inhibit the proliferation of cancer cells in vitro and in vivo in a variety of malignancies (4)(5)(6)(7)(8)(9), including lymphoma (10)(11)(12)(13)(14). HDACIs are hypothesized to suppress cancer cell proliferation through histone hyperacetylation, resulting…”