Pdtm-07. Systematic Drug Identifies Digoxin as a Drug That Prolongs Survival in Pdox Models of Groups 3 and 4 Medulloblastoma at Clinically Relevant Doses
Year: 2017
Type: conference-abstract
Abstract: Medulloblastoma (MB) is the most common malignant brain tumor of childhood. While the current standard care for MB leads to long term survival in approximately 75 % of patients; recurrent and refractory MB continues to have dismal outcomes and long term survivors face significant treatment-related sequelae. Drug repositioning for known drugs is a promising potential strategy which allows for accelerated translation into the clinical setting. A non-parametric, bootstrapping based simulated annealing (NPBSA) algorithm was employed to identify driver signaling pathways for over 1,800 patients with Group 3 and Group 4 MB through an integrative analysis on their mRNA expression, DNA-copy number, DNA-methylation and DNA-seq profiles. Drug functional networks then were constructed based on gene expression profiles under drug treatment and chemical structures. These were clustered into drug modules with potential mechanisms of action. By evaluating the targeted effects of 1,309 drugs from connectivity map database, we identified multiple cardiac glycosides as potential drug candidates for Group 3 and 4 MB subtypes. These findings were first validated in multiple MB-derived cell lines which showed high rates of growth inhibition by cardiac glycosides compared to controls. Patient-derived orthotopic-xenograft (PDOX) models of Group 3 (ICb-2555MB) and 4 MB (ICb-1078MB) were subsequently treated with digoxin (2 mg/kg i.p.) for 2 cycles of 14 days. Digoxin treatment significantly prolonged survival in both models compared to untreated controls (p=0.001; p=0.031). Studies using the Group 3 model further demonstrated that the observed survival benefit is synergistic with radiation and that prolonged dosing (daily treatment for 60 days) further improves median survival. Finally, average digoxin trough levels in treated mice (2.4 ng/mL +/- 0.4) were similar to target levels used in heart failure patients taking digoxin (0.8- 2 ng/mL) suggesting the potential for rapid translation of these findings into a clinical setting.
Source: Neuro-Oncology
Authors: Sarah Injac, Lei Huang, Hong Zhao, Lin Qi, Mari Kogiso, Chris Man, Xiao-Nan Li, Ching Lau, Stephen Wong
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2767860596