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 language | English (US) |
|---|---|
| Article number | eaat0150 |
| Journal | Science translational medicine |
| Volume | 10 |
| Issue number | 464 |
| DOIs | |
| State | Published - Oct 24 2018 |
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ASJC Scopus subject areas
- Medicine(all)
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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 journal › Article
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85055515819&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055515819&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aat0150
DO - 10.1126/scitranslmed.aat0150
M3 - Article
C2 - 30355798
AN - SCOPUS:85055515819
VL - 10
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 464
M1 - eaat0150
ER -