Integrative rare disease biomedical profile based network supporting drug repurposing or repositioning, a case study of glioblastoma

Abstract

Background: Glioblastoma (GBM) is the most aggressive and common malignant primary brain tumor; however, treatment remains a significant challenge. This study aims to identify drug repurposing or repositioning candidates for GBM by developing an integrative rare disease profile network containing heterogeneous types of biomedical data.

Methods: We developed a Glioblastoma-based Biomedical Profile Network (GBPN) by extracting and integrating biomedical information pertinent to GBM-related diseases from the NCATS GARD Knowledge Graph (NGKG). We further clustered the GBPN based on modularity classes which resulted in multiple focused subgraphs, named mc_GBPN. We then identified high-influence nodes by performing network analysis over the mc_GBPN and validated those nodes that could be potential drug repurposing or repositioning candidates for GBM.

Results: We developed the GBPN with 1,466 nodes and 107,423 edges and consequently the mc_GBPN with forty-one modularity classes. A list of the ten most influential nodes were identified from the mc_GBPN. These notably include Riluzole, stem cell therapy, cannabidiol, and VK-0214, with proven evidence for treating GBM.

Conclusion: Our GBM-targeted network analysis allowed us to effectively identify potential candidates for drug repurposing or repositioning. Further validation will be conducted by using other different types of biomedical and clinical data and biological experiments. The findings could lead to less invasive treatments for glioblastoma while significantly reducing research costs by shortening the drug development timeline. Furthermore, this workflow can be extended to other disease areas.

Keywords: Data integration; Drug repurposing or repositioning; Glioblastoma; Network analysis.

Fig. 1

Workflow for identifying drug repurposing or repositioning candidates for GBM.

Fig. 2

Familial Alzheimer Disease-based subgraph derived from the NGKG. Orange nodes denote diseases, blue nodes denote genes, and purple nodes denote drugs. Familial Alzheimer Disease is highlighted in yellow

Fig. 3

A node containing Lafora disease is merged with nodes connected to it by an edge label of “I_CODE”: two Lafora disease related genes, the EPM2A gene, the EPM2B gene, and Metformin, a treatment that has been used for Lafora disease. The gray node is one of the merged nodes in the GBPN.

Fig. 4

High-influence nodes identified by degree, closeness, betweenness, eigenvector, and PageRank centrality in mc_GBPN with an index of 0. The nodes displayed have a strong relationship to white matter-related conditions (as does GBM). Note that several nodes have high centrality scores across multiple measures; these nodes have a higher potential for drug repurposing or repositioning