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- Title
Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma.
- Authors
Huang, Lei; Garrett Injac, Sarah; Cui, Kemi; Braun, Frank; Lin, Qi; Du, Yuchen; Zhang, Huiyuan; Kogiso, Mari; Lindsay, Holly; Zhao, Sibo; Baxter, Patricia; Adekunle, Adesina; Man, Tsz-Kwong; Zhao, Hong; Li, Xiao-Nan; Lau, Ching C.; Wong, Stephen T. C.
- Abstract
Systematic drug repositioning identifies digoxin as a potential treatment for groups 3 and 4 medulloblastoma. Digoxin on the brain: Groups 3 and 4 medulloblastoma (MB) are highly heterogeneous in nature and have therefore proven difficult to target, resulting in corresponding meagre survival rates. Using a sophisticated systematic drug repositioning approach, Huang et al. identified the already-approved drug digoxin as a possible treatment for these MB subtypes. Application of digoxin to orthotopic patient-derived xenograft models produced an increase in survival; this increase in survival was further extended upon combining digoxin treatment with radiation, and, importantly, occurred at blood concentrations of digoxin that might be feasible in patients. These findings could mean a possible inroads in improving outcome for patients with these hard-to-treat cancers. 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.
- Subjects
MEDULLOBLASTOMA; BRAIN tumors; DIGOXIN; CANCER; DRUGS
- Publication
Science Translational Medicine, 2018, Vol 10, Issue 464, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aat0150