A Network Polypharmacology Approach to Drug Repurposing for Diffuse Intrinsic Pontine Glioma [article]

Finlay MacLean, Pan Pantziarka, Javad Nazarian, Jabe Wilson
2020 bioRxiv   pre-print
Despite five decades of clinical investigations, there is currently no effective treatment for children diagnosed with Diffuse Intrinsic Pontine Glioma (DIPG). We now understand that DIPGs share the same histone 3 mutation and fatal prognosis as other diffuse midline gliomas (DMGs), which led to the introduction of a new entity referred to as DMG, H3 K27M mutant. Indeed, therapeutics indicated for other brain neoplasms have proven ineffective for DIPGs. We posit that by using a
more » ... al approach to determine drug combinations that target distinct mechanistic pathways of DIPG, it is more likely that an efficacious treatment will be developed. Using FDA-approved drugs as an indication for viability of a drug pair for combinatorial use, we developed an embedding-based link-prediction model trained on a drug-disease regulation network, to predict the complementary relationship between a drug pair. To further understand the regulatory mechanisms of these potential drug combinations, we explored the regulatory action of these drugs upon statistically significant biological processes and molecular functions that are in turn misregulated in the disease state of phylogenetically similar gliomas to DIPG. Next, we constructed a regulatory network of these regulators illustrating a negative correlation between network proximity and overlap of direct targets, regulators, pathways and biological processes. We replicate research that finds an optimal distance between drugs in this regulatory network for both FDA-approved and synergistic drugs, although we deem the embedding model more performant. Finally, we highlight the individual importance of all disease-host protein regulators in notable pathways, by constructing protein-protein interaction networks for each pathway and calculating the centrality of each regulatory gene. We believe this newly formed knowledge of drug pairs and their regulatory pathways, will help researchers in identifying an efficacious treatment for this disease.
doi:10.1101/2020.06.14.150714 fatcat:vwknosbe3zduvmhgb7xielo3oe