Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models.
Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models.
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DOI：
10.1371/journal.pone.0169485
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Becher OJ
中科院分区：
文献类型：
--
作者：
Hennika T;Hu G;Olaciregui NG;Barton KL;Ehteda A;Chitranjan A;Chang C;Gifford AJ;Tsoli M;Ziegler DS;Carcaboso AM;Becher OJ
弥漫性内在脑桥胶质瘤（DIPG）或高级别脑干胶质瘤（BSG）是儿童脑肿瘤相关死亡的主要原因之一。尽管为提高生存率做出了许多努力，但其预后仍然很差。Panobinostat是一种组蛋白去乙酰化酶抑制剂，是一种靶向药物，最近显示出临床前疗效，并进入I期临床试验，用于治疗复发性或进行性DIPG儿童。通过PDGF-B信号、p53缺失和异位H3.3-K27M或H3.3-WT表达驱动的遗传BSG小鼠模型和H3.3-K27M原位DIPG异种移植模型，开展了一项合作的临床前研究，以证实和扩展先前发表的关于panobinostat体外和体内功效的研究结果。在体外，panobinostat能有效抑制人和小鼠DIPG细胞的增殖、活力和克隆原性，并诱导细胞凋亡。对基因工程荷瘤小鼠短期全身给药后的体内组织分析表明，药物到达脑干肿瘤组织的程度大于正常脑组织，肿瘤细胞增殖减少，H3乙酰化水平升高，显示出靶向抑制作用。长期连续每日使用10或20 mg/kg的panobinostat治疗遗传和原位异种移植模型均导致显著的毒性。然而，与给药小鼠相比，减少且耐受良好的panobinostat剂量并没有延长总生存期。我们的合作临床前研究证实，panobinostat在体外和小鼠体内短期疗效研究中是一种有效的针对DIPG人类和小鼠肿瘤细胞的靶向药物，但对携带h3.3 - k27m突变肿瘤的小鼠的生存没有显著影响。我们认为这可能是由于全身给药panobinostat的毒性，需要剂量递减。
Diffuse intrinsic pontine glioma (DIPG), or high-grade brainstem glioma (BSG), is one of the major causes of brain tumor-related deaths in children. Its prognosis has remained poor despite numerous efforts to improve survival. Panobinostat, a histone deacetylase inhibitor, is a targeted agent that has recently shown pre-clinical efficacy and entered a phase I clinical trial for the treatment of children with recurrent or progressive DIPG. A collaborative pre-clinical study was conducted using both a genetic BSG mouse model driven by PDGF-B signaling, p53 loss, and ectopic H3.3-K27M or H3.3-WT expression and an H3.3-K27M orthotopic DIPG xenograft model to confirm and extend previously published findings regarding the efficacy of panobinostat in vitro and in vivo. In vitro, panobinostat potently inhibited cell proliferation, viability, and clonogenicity and induced apoptosis of human and murine DIPG cells. In vivo analyses of tissue after short-term systemic administration of panobinostat to genetically engineered tumor-bearing mice indicated that the drug reached brainstem tumor tissue to a greater extent than normal brain tissue, reduced proliferation of tumor cells and increased levels of H3 acetylation, demonstrating target inhibition. Extended consecutive daily treatment of both genetic and orthotopic xenograft models with 10 or 20 mg/kg panobinostat consistently led to significant toxicity. Reduced, well-tolerated doses of panobinostat, however, did not prolong overall survival compared to vehicle-treated mice. Our collaborative pre-clinical study confirms that panobinostat is an effective targeted agent against DIPG human and murine tumor cells in vitro and in short-term in vivo efficacy studies in mice but does not significantly impact survival of mice bearing H3.3-K27M-mutant tumors. We suggest this may be due to toxicity associated with systemic administration of panobinostat that necessitated dose de-escalation.
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DOI：
10.1073/pnas.1101657108
发表时间：
2011-03-15
影响因子：
11.1
作者：
Monje, Michelle;Mitra, Siddhartha S.;Beachy, Philip A.
通讯作者：
Beachy, Philip A.
影响因子：
30.8
作者：
Wu, Gang;Broniscer, Alberto;McEachron, Troy A.;Lu, Charles;Paugh, Barbara S.;Becksfort, Jared;Qu, Chunxu;Ding, Li;Huether, Robert;Parker, Matthew;Zhang, Junyuan;Gajjar, Amar;Dyer, Michael A.;Mullighan, Charles G.;Gilbertson, Richard J.;Mardis, Elaine R.;Wilson, Richard K.;Downing, James R.;Ellison, David W.;Zhang, Jinghui;Baker, Suzanne J.
通讯作者：
Baker, Suzanne J.
影响因子：
3.7
作者：
Barton KL;Misuraca K;Cordero F;Dobrikova E;Min HD;Gromeier M;Kirsch DG;Becher OJ
通讯作者：
Becher OJ
影响因子：
30.8
作者：
Wu G;Diaz AK;Paugh BS;Rankin SL;Ju B;Li Y;Zhu X;Qu C;Chen X;Zhang J;Easton J;Edmonson M;Ma X;Lu C;Nagahawatte P;Hedlund E;Rusch M;Pounds S;Lin T;Onar-Thomas A;Huether R;Kriwacki R;Parker M;Gupta P;Becksfort J;Wei L;Mulder HL;Boggs K;Vadodaria B;Yergeau D;Russell JC;Ochoa K;Fulton RS;Fulton LL;Jones C;Boop FA;Broniscer A;Wetmore C;Gajjar A;Ding L;Mardis ER;Wilson RK;Taylor MR;Downing JR;Ellison DW;Zhang J;Baker SJ
通讯作者：
Baker SJ
影响因子：
50.3
作者：
Bender, Sebastian;Tang, Yujie;Pfister, Stefan M.
通讯作者：
Pfister, Stefan M.