Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma

Lei Huang, Sarah Garrett Injac, Kemi Cui, Frank Braun, Lin Qi, Yuchen Du, Huiyuan Zhang, Mari Kogiso, Holly Lindsay, Sibo Zhao, Patricia Baxter, Adesina Adekunle, Tsz Kwong Man, Hong Zhao, Xiaonan Li, Ching C. Lau, Stephen T.C. Wong*

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbereaat0150
JournalScience translational medicine
Volume10
Issue number464
DOIs
StatePublished - Oct 24 2018

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Drug Repositioning
Medulloblastoma
Systems Biology
Digoxin
Group Psychotherapy
Cardiac Glycosides
Therapeutics
Pharmaceutical Preparations
Treatment Failure
Heterografts
Brain Neoplasms
Heart Failure
Survival
Growth

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Huang, Lei ; Injac, Sarah Garrett ; Cui, Kemi ; Braun, Frank ; Qi, Lin ; Du, Yuchen ; Zhang, Huiyuan ; Kogiso, Mari ; Lindsay, Holly ; Zhao, Sibo ; Baxter, Patricia ; Adekunle, Adesina ; Man, Tsz Kwong ; Zhao, Hong ; Li, Xiaonan ; Lau, Ching C. ; Wong, Stephen T.C. / Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma. In: Science translational medicine. 2018 ; Vol. 10, No. 464.
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title = "Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma",
abstract = "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.",
author = "Lei Huang and Injac, {Sarah Garrett} and Kemi Cui and Frank Braun and Lin Qi and Yuchen Du and Huiyuan Zhang and Mari Kogiso and Holly Lindsay and Sibo Zhao and Patricia Baxter and Adesina Adekunle and Man, {Tsz Kwong} and Hong Zhao and Xiaonan Li and Lau, {Ching C.} and Wong, {Stephen T.C.}",
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Huang, L, Injac, SG, Cui, K, Braun, F, Qi, L, Du, Y, Zhang, H, Kogiso, M, Lindsay, H, Zhao, S, Baxter, P, Adekunle, A, Man, TK, Zhao, H, Li, X, Lau, CC & Wong, STC 2018, 'Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma', Science translational medicine, vol. 10, no. 464, eaat0150. https://doi.org/10.1126/scitranslmed.aat0150

Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma. / Huang, Lei; Injac, Sarah Garrett; Cui, Kemi; Braun, Frank; Qi, Lin; Du, Yuchen; Zhang, Huiyuan; Kogiso, Mari; Lindsay, Holly; Zhao, Sibo; Baxter, Patricia; Adekunle, Adesina; Man, Tsz Kwong; Zhao, Hong; Li, Xiaonan; Lau, Ching C.; Wong, Stephen T.C.

In: Science translational medicine, Vol. 10, No. 464, eaat0150, 24.10.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma

AU - Huang, Lei

AU - Injac, Sarah Garrett

AU - Cui, Kemi

AU - Braun, Frank

AU - Qi, Lin

AU - Du, Yuchen

AU - Zhang, Huiyuan

AU - Kogiso, Mari

AU - Lindsay, Holly

AU - Zhao, Sibo

AU - Baxter, Patricia

AU - Adekunle, Adesina

AU - Man, Tsz Kwong

AU - Zhao, Hong

AU - Li, Xiaonan

AU - Lau, Ching C.

AU - Wong, Stephen T.C.

PY - 2018/10/24

Y1 - 2018/10/24

N2 - 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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