Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomas.
Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomas.
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DOI：
10.1002/lary.22392
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发表时间：
2012-01
期刊：
影响因子：
2.6
通讯作者：
Welling, D. Bradley
中科院分区：
文献类型：
--
作者：
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
关键词：
最近的研究表明，前庭神经鞘瘤（VS）依赖于PI 3-激酶/AKT激活，以促进细胞增殖和存活;因此，靶向AKT可能提供新的治疗选择。我们先前已经表明，AR 42，一种新的组蛋白去乙酰化酶抑制剂，在与AKT失活相关的剂量下，在体外有效地抑制VS生长。本研究的目的是翻译：1）检查AR 42对体内肿瘤生长的最终生物学效应，2）验证AKT作为其体内分子靶标，3）确定AR 42是否穿透血脑屏障（BBB），以及4）研究AR 42的药物毒性特征。在小鼠体内研究中，在小鼠神经鞘瘤同种异体移植物和人前庭神经鞘瘤异种移植物中口服给予AR 42。MRI用于量化肿瘤体积的变化，而细胞内分子靶点使用免疫组织化学进行分析。血脑屏障（BBB）渗透进行了测定，血液化学测量和组织学研究用于评价毒性。在与AKT去磷酸化、细胞周期停滞和凋亡相关的剂量下，AR 42显著降低神经鞘瘤植入物的生长。AR 42穿透BBB，喂食AR 42 6个月的野生型小鼠行为正常，体重适当增加。在AR 42治疗3个月和6个月后进行的血液化学研究和器官组织学研究显示无临床显著异常。AR 42在与AKT通路抑制相关的剂量下抑制神经鞘瘤生长。这种口服生物可利用的药物渗透血脑屏障，耐受性良好，代表了一种新的候选翻译人类VS临床试验。
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. In vivo mouse studies 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. 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. 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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影响因子：
5.7
作者：
Cao, Z. Alexander;Bass, Kathryn E.;Buggy, Joseph J.
通讯作者：
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影响因子：
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DOI：
10.1084/jem.121.6.873
发表时间：
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期刊：
The Journal of experimental medicine
影响因子：
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作者：
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通讯作者：
LEVINE BB
DOI：
10.1152/ajpgi.00575.2004
发表时间：
2005-10-01
影响因子：
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作者：
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通讯作者：
Hodin, RA