NCATS Team Creates Novel Computational Pipeline to Find New Ways to Treat Glioblastoma

Glioblastoma is a rare, aggressive brain cancer with no satisfactory therapies and a five-year survival rate less than 5%. (Shutterstock)

March 10, 2025

A new approach by NCATS scientists could help find existing drugs that may work against glioblastoma (GBM). GBM is a rare, aggressive brain cancer with no adequate therapies and a five-year survival rate below 5%.

To find already approved drugs that could be repurposed against GBM, NCATS scientists created a computational pipeline to detect and study promising treatments. That pipeline identifies drugs based on their ability to reverse the GBM gene expression profile (GGEP) the scientists designed. The GGEP describes how GBM cells use the information in genes to create proteins. The approach looks at how diseases affect cells’ gene expression and how drugs alter that process. The study appeared in the Journal of Translational Medicine.

To build the GGEP, NCATS scientists studied multi-omics data from GBM patient samples. Multi-omics includes such information as how cells make RNA copies of their DNA (transcriptomics) and how cells’ proteins work (proteomics). That multi-omics analysis revealed 318 suspect genes expressed abnormally in GBM cells.

The team then matched that GGEP with existing drugs whose mechanisms of action might reverse the GGEP. The team used the iLINCS database to find drugs that showed promise against the target GGEP. iLINCS contains information about how drugs affect the way a cell expresses its genes. The analysis revealed 119 existing drugs that could affect GBM gene expression — 21 of which have been tested in GBM-related clinical trials.

The NCATS team developed two scores that measure how well a candidate drug reverses the GGEP. Based on those scores, the team focused on five candidates for GBM: ciclopirox, prochlorperazine, clofarabine, tacrolimus and tigecycline. They also used NCATS’ Biomedical Data Translator to see how those drugs might work against GBM. The Biomedical Data Translator analyzes a vast range of biomedical research and clinical data sources to reveal novel relationships between chemical compounds, drugs and diseases or genes.

The team tested 11 concentrations of each drug candidate in GBM cells and healthy brain cells in the lab. Clofarabine and ciclopirox proved to be best at targeting GBM cells while sparing healthy cells. Both drugs beat the current standard GBM treatment, temozolomide, in cell-culture experiments.

The NCATS scientists plan to strengthen GGEP’s predictive power by adding more drug-activity databases. They will also include data from a high-throughput proteomics platform built in-house to find promising repurposed drugs for GBM and other rare diseases. To speed future drug repurposing efforts in rare diseases, the research team identified a need for the creation of a repository of rare disease–based data on gene expression and other cell processes.