Effective inhibition of MYC-amplified group 3 medulloblastoma by FACT-targeted curaxin drug CBL0137.
Effective inhibition of MYC-amplified group 3 medulloblastoma by FACT-targeted curaxin drug CBL0137.
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FACT 靶向 curaxin 药物 CBL0137 有效抑制 MYC 扩增的第 3 组髓母细胞瘤
DOI：
10.1038/s41419-020-03201-6
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发表时间：
2020-12-02
影响因子：
9
通讯作者：
Ma J
中科院分区：
文献类型：
--
作者：
Wang J;Sui Y;Li Q;Zhao Y;Dong X;Yang J;Liang Z;Han Y;Tang Y;Ma J
髓母细胞瘤（MB）是最常见的儿童恶性脑肿瘤，可分为四个主要的分子亚组。具有MYC扩增的第3组MB（MYCamp-G3-MB）已被证明是高度侵袭性的，并且表现出最差的预后，这表明最迫切地需要新的有效治疗。一些表观遗传靶向治疗策略最近已被证明可有效治疗MYCamp-G3-MB的临床前模型，包括BET抑制、HDAC抑制和SETD 8抑制，为进一步研究揭示了一个有希望的方向。在这项研究中，我们对公开的MB数据集以及原代MYCamp-G3-MB系的功能基因组筛选数据集进行了系统的生物信息学分析，以寻找表观遗传调节剂中的其他潜在治疗靶点。我们将组蛋白-伴侣蛋白FACT复合物的亚基SSRP 1鉴定为首选药物靶标候选物，因为它在多个MYCamp-G3-MB系的全基因组CRISPR-Cas9筛选中具有高度癌症依赖性;与正常小脑和大多数其他MB亚型相比，在MYCamp-G3-MB中显著上调;其较高的表达与较差的预后相关;它有一种穿透血脑屏障的靶向药物，已经进入早期人体临床试验。然后，我们利用RNA干扰方法来验证SSRP 1在多个MYCamp-G3-MB系中的癌症依赖性，并进一步证实了FACT靶向Curaxin药物CBL 0137在体外和体内治疗MYCamp-G3-MB临床前模型（包括原位颅内异种移植模型）的治疗功效。从机制上讲，转录组分析显示CBL 0137优先抑制细胞周期和DNA修复相关的生物过程。此外，它选择性地破坏MYCamp-G3-MB的两个关键致癌转录因子MYCandNEUROD 1的转录，通过从它们的启动子区域消耗FACT复合物。总之，我们的研究表明，靶向FACT-CBL 0137有效地治疗MYCamp-G3-MB，提出了另一种有希望的针对最具破坏性的MB形式的表观遗传靶向治疗策略。
Medulloblastoma (MB) is the most common malignant pediatric brain tumor that can be categorized into four major molecular subgroups. Group 3 MB withMYCamplification (MYCamp-G3-MB) has been shown to be highly aggressive and exhibited worst prognosis, indicating the need for novel effective therapy most urgently. A few epigenetic targeted therapeutic strategies have recently been proven to effectively treat preclinical models of MYCamp-G3-MB, including BET inhibition, HDAC inhibition and SETD8 inhibition, unveiling a promising direction for further investigation. In this study, we carried out systemic bioinformatic analyses of public-available MB datasets as well as functional genomic screening datasets of primary MYCamp-G3-MB lines to search for other potential therapeutic targets within epigenetic modulators. We identified SSRP1, a subunit of histone-chaperone FACT complex, to be the top drug target candidate as it is highly cancer-dependent in whole-genome CRISPR-Cas9 screening across multiple MYCamp-G3-MB lines; significantly upregulated in MYCamp-G3-MB compared to normal cerebellum and most of the rest MB subtypes; its higher expression is correlated with worse prognosis; and it has a blood-brain-barrier penetrable targeted drug that has entered early phase human clinical trials already. Then we utilized RNA-interference approach to verify the cancer-dependency of SSRP1 in multiple MYCamp-G3-MB lines and further confirmed the therapeutic efficacy of FACT-targeted curaxin drug CBL0137 on treating preclinical models of MYCamp-G3-MB in vitro and in vivo, including an orthotopic intracranial xenograft model. Mechanistically, transcriptome analyses showed CBL0137 preferentially suppressed cell-cycle and DNA-repair related biological processes. Moreover, it selectively disrupted transcription ofMYCandNEUROD1, two critical oncogenic transcription factors of MYCamp-G3-MB, via depleting FACT complex from their promoter regions. In summary, our study demonstrates FACT-targeted CBL0137 works effectively on treating MYCamp-G3-MB, presenting another promising epigenetic-targeted therapeutic strategy against the most devastating form of MB.
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SSRP1沉默通过MAPK信号通路抑制人胶质瘤细胞的增殖和恶性
影响因子：
4.2
作者：
Liao J;Tao X;Ding Q;Liu J;Yang X;Yuan FE;Yang JA;Liu B;Xiang GA;Chen Q
通讯作者：
Chen Q
影响因子：
17.1
作者：
Carter DR;Murray J;Cheung BB;Gamble L;Koach J;Tsang J;Sutton S;Kalla H;Syed S;Gifford AJ;Issaeva N;Biktasova A;Atmadibrata B;Sun Y;Sokolowski N;Ling D;Kim PY;Webber H;Clark A;Ruhle M;Liu B;Oberthuer A;Fischer M;Byrne J;Saletta F;Thwe le M;Purmal A;Haderski G;Burkhart C;Speleman F;De Preter K;Beckers A;Ziegler DS;Liu T;Gurova KV;Gudkov AV;Norris MD;Haber M;Marshall GM
通讯作者：
Marshall GM
影响因子：
16
作者：
Bellelli R;Borel V;Logan C;Svendsen J;Cox DE;Nye E;Metcalfe K;O'Connell SM;Stamp G;Flynn HR;Snijders AP;Lassailly F;Jackson A;Boulton SJ
通讯作者：
Boulton SJ
影响因子：
4.8
作者：
Kuzan-Fischer, ClaudiaM;Stucklin, Ana S. Guerreiro;Taylor, Michael D.
通讯作者：
Taylor, Michael D.
影响因子：
4
作者：
Belotserkovskaya, R;Reinberg, D
通讯作者：
Reinberg, D