The first-in-class alkylating deacetylase inhibitor molecule tinostamustine shows antitumor effects and is synergistic with radiotherapy in preclinical models of glioblastoma.
The first-in-class alkylating deacetylase inhibitor molecule tinostamustine shows antitumor effects and is synergistic with radiotherapy in preclinical models of glioblastoma.
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DOI：
10.1186/s13045-018-0576-6
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发表时间：
2018-02-27
影响因子：
28.5
通讯作者：
Mehrling T
中科院分区：
文献类型：
--
作者：
Festuccia C;Mancini A;Colapietro A;Gravina GL;Vitale F;Marampon F;Delle Monache S;Pompili S;Cristiano L;Vetuschi A;Tombolini V;Chen Y;Mehrling T
使用烷化剂如替莫唑胺与放射治疗（RT）联合是胶质母细胞瘤（GBM）的治疗标准。该方案适度地延长了总生存期，如果考虑到仍然令人沮丧的预后，迫切需要进一步改善，特别是在患有O 6-甲基鸟嘌呤-DNA-甲基转移酶（MGMT）未甲基化肿瘤的患者中，其中标准治疗的益处较少。替诺莫司汀（EDO-S101）是一种一流的烷基化脱乙酰酶抑制剂（AK-DACi）分子，将苯达莫司汀的DNA损伤作用与全功能泛组蛋白脱乙酰酶（HDAC）融合在一起。抑制剂伏立诺他，在一个全新的化学实体。已通过使用13种GBM细胞系和7种患者来源的GBM增殖/干细胞系在体外对替诺莫司汀在GBM模型中进行了测试。将U87 MG和U251 MG（MGMT阴性）以及T98 G（MGMT阳性）皮下注射到裸鼠中，而荧光素酶阳性U251 MG细胞和患者来源的GBM干细胞系（CSC-5）通过原位脑内体内实验进行评估。我们证明了替诺莫司汀具有比单独伏立诺他和苯达莫司汀所观察到的更强的抗增殖和促凋亡作用，并且与它们的组合相似并且与MGMT表达无关。此外，我们观察到单次治疗和替莫唑胺作为对照的放射增敏作用更强，这是由于γ H2 AX的表达减少和消失时间增加，表明信号和DNA修复减少。这与更高的caspase-3活化和RT介导的自噬减少有关。在体内，替诺莫司汀延长了至进展时间（TTP），这与RT具有相加/协同作用。替诺莫司汀在原位脑内模型中具有显著的治疗活性，可抑制肿瘤生长并延长DFS（无病生存期）和OS（总生存期），上级苯达莫司汀、RT和替莫唑胺，并显示出更强的放射敏感性。我们的数据表明，替诺莫司汀值得进一步研究与胶质母细胞瘤患者。本文的在线版本（10.1186/s13045-018-0576-6）包含补充材料，可供授权用户使用。
The use of alkylating agents such as temozolomide in association with radiotherapy (RT) is the therapeutic standard of glioblastoma (GBM). This regimen modestly prolongs overall survival, also if, in light of the still dismal prognosis, further improvements are desperately needed, especially in the patients with O6-methylguanine-DNA-methyltransferase (MGMT) unmethylated tumors, in which the benefit of standard treatment is less. Tinostamustine (EDO-S101) is a first-in-class alkylating deacetylase inhibitor (AK-DACi) molecule that fuses the DNA damaging effect of bendamustine with the fully functional pan-histone deacetylase (HDAC) inhibitor, vorinostat, in a completely new chemical entity. Tinostamustine has been tested in models of GBM by using 13 GBM cell lines and seven patient-derived GBM proliferating/stem cell lines in vitro. U87MG and U251MG (MGMT negative), as well as T98G (MGMT positive), were subcutaneously injected in nude mice, whereas luciferase positive U251MG cells and patient-derived GBM stem cell line (CSCs-5) were evaluated the orthotopic intra-brain in vivo experiments. We demonstrated that tinostamustine possesses stronger antiproliferative and pro-apoptotic effects than those observed for vorinostat and bendamustine alone and similar to their combination and irrespective of MGMT expression. In addition, we observed a stronger radio-sensitization of single treatment and temozolomide used as control due to reduced expression and increased time of disappearance of γH2AX indicative of reduced signal and DNA repair. This was associated with higher caspase-3 activation and reduction of RT-mediated autophagy. In vivo, tinostamustine increased time-to-progression (TTP) and this was additive/synergistic to RT. Tinostamustine had significant therapeutic activity with suppression of tumor growth and prolongation of DFS (disease-free survival) and OS (overall survival) in orthotopic intra-brain models that was superior to bendamustine, RT and temozolomide and showing stronger radio sensitivity. Our data suggest that tinostamustine deserves further investigation in patients with glioblastoma. The online version of this article (10.1186/s13045-018-0576-6) contains supplementary material, which is available to authorized users.
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影响因子：
11
作者：
Hsu CC;Chang WC;Hsu TI;Liu JJ;Yeh SH;Wang JY;Liou JP;Ko CY;Chang KY;Chuang JY
通讯作者：
Chuang JY
影响因子：
28.5
作者：
Gravina GL;Mancini A;Marampon F;Colapietro A;Delle Monache S;Sferra R;Vitale F;Richardson PJ;Patient L;Burbidge S;Festuccia C
通讯作者：
Festuccia C
影响因子：
4.7
作者：
Gielen, Paul R.;Aftab, Qurratulain;Sin, Wun Chey
通讯作者：
Sin, Wun Chey
影响因子：
2.2
作者：
Chandrashekar, Devaraj V.;Suresh, Ponnayyan S.;Srinivas, Nuggehally R.
通讯作者：
Srinivas, Nuggehally R.
影响因子：
15.9
作者：
Blough, Michael D.;Westgate, Morgan R.;Cairncross, J. Gregory
通讯作者：
Cairncross, J. Gregory