Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma.
Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma.
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DOI：
10.1126/scitranslmed.aat0150
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发表时间：
2018-10-24
影响因子：
17.1
通讯作者：
Wong STC
中科院分区：
文献类型：
--
作者：
Huang L;Garrett Injac S;Cui K;Braun F;Lin Q;Du Y;Zhang H;Kogiso M;Lindsay H;Zhao S;Baxter P;Adekunle A;Man TK;Zhao H;Li XN;Lau CC;Wong STC
Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Although outcomes have improved in recent decades, new treatments are still needed to improve survival and reduce treatment-related complications. The MB subtypes groups 3 and 4 represent a particular challenge due to their intragroup heterogeneity, which limits the options for “rational” targeted therapies. Here, we report a systems biology approach to drug repositioning that integrates a nonparametric, bootstrapping-based simulated annealing algorithm and a 3D drug functional network to characterize dysregulated driver signaling networks, thereby identifying potential drug candidates. From more than 1300 drug candidates studied, we identified five members of the cardiac glycoside family as potentially inhibiting the growth of groups 3 and 4 MB and subsequently confirmed this in vitro. Systemic in vivo treatment of orthotopic patient-derived xenograft (PDX) models of groups 3 and 4 MB with digoxin, a member of the cardiac glycoside family approved for the treatment of heart failure, prolonged animal survival at plasma concentrations known to be tolerated in humans. These results demonstrate the power of a systematic drug repositioning method in identifying a potential treatment for MB. Our strategy could potentially be used to accelerate the repositioning of treatments for other human cancers that lack clearly defined rational targets.
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影响因子：
2
作者：
Gottardo, Nicholas G;Gajjar, Amar
通讯作者：
Gajjar, Amar
DOI：
10.1093/bioinformatics/btu278
发表时间：
2014-06-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Huang L;Li F;Sheng J;Xia X;Ma J;Zhan M;Wong ST
通讯作者：
Wong ST
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
50.3
作者：
Chae YC;Vaira V;Caino MC;Tang HY;Seo JH;Kossenkov AV;Ottobrini L;Martelli C;Lucignani G;Bertolini I;Locatelli M;Bryant KG;Ghosh JC;Lisanti S;Ku B;Bosari S;Languino LR;Speicher DW;Altieri DC
通讯作者：
Altieri DC
DOI：
10.1016/j.bbrc.2008.06.121
发表时间：
2008-09-12
影响因子：
3.1
作者：
Chiellini, Chiara;Grenningloh, Gabriele;Amri, Ez-Zoubir
通讯作者：
Amri, Ez-Zoubir