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.

A multiplexed bioluminescent reporter for sensitive and non-invasive tracking of DNA double strand break repair dynamicsin vitroandin vivo

“…Given that RAD51 activity confers resistance to radiation therapy, concomitant treatment of GBM with cardiac glycosides could potentially increase radiosensitivity. In fact, several members of the cardiac glycoside family have been previously reported to increase tumour cell death following radiation therapy (67)(68)(69)(70)(71).…”

The Na+/K+ATPase Regulates Glycolysis and Modifies Immune Metabolism in Tumors

“…Cardiac glycosides have been shown to exhibit antineoplastic effects in numerous settings 20,21,35 , which have been attributed to a myriad of sources such disruption of proton gradients 32 and activation of kinases that physically interact with the sodium-potassium pump (i.e. Na + /K + ATPase "signalosome") [62][63][64] .…”

“…We then orthotopically injected these cells into the right gastrocnemius muscle of syngeneic 129/SvJae mice. Upon tumor palpation (approximately 11 days after injection), we treated mice with a previously reported dose 35 of 2 mg/kg digoxin every 24 hours and collected tumors as well as healthy tissues after administration of the fourth dose ( Figure 3A). Of note, while this treatment regimen appeared to trend towards tumor growth inhibition, treated mice exhibited some weight loss upon daily digoxin treatment ( Figure S2D and S2E) although no other physiological or behavioral signs of toxicity were observed.…”

Preclinical Models of Craniospinal Irradiation for Medulloblastoma

“…In contrast, a cumulative CSI dose of 10 Gy delivered over 1 week extended the lifespan of mice harboring an SHH PDOX (by approximately 40 days) and of those harboring a G3 PDOX (by approximately 90 days), but all of these mice subsequently experienced tumor recurrence and ultimately succumbed to progressive disease. More recent work by Huang et al incorporated CSI and boost irradiation in a preclinical setting to explore potential combination therapy in G3 and G4 medulloblastoma PDOX models [79]. Using the RS-2000 Biological Irradiator (Rad Source Technologies) and custom-made lead shielding, they administered CSI in 2 Gy fractions over 5 days, followed by an additional 10 Gy delivered over 5 days specifically to the tumor injection site within the cerebellum.…”