When Old Drugs Learn New Tricks: A Smarter Way to Fight Brain Tumors

Why repurposing familiar drugs for glioblastoma matters now

Glioblastoma multiforme is one of the most aggressive types of brain cancer, and despite treatment with surgery, radiation, and the chemotherapy drug Temozolomide, survival rates remain low. Tumors often recur and show resistance to standard therapy, which leaves patients and clinicians with limited options. Prof Sudeshna Mukherjee, Prof. Rajdeep Chowdhury, Prof. Syamantak Majumder, Prof. Aniruddha Roy, Prof. Shibasish Chowdhury and their team from BITS Pilani, Pilani Campus in the Departments of Biological Sciences and Pharmacy investigated whether existing medicines could be redirected against glioblastoma. Their central idea is straightforward; if an approved or widely studied drug can cross the blood-brain barrier and reverse the disease’s activity patterns, it might move to clinical testing faster than a brand new molecule. The study identifies two such candidates and explores how they act on glioblastoma cells in detail.

What the study set out to do

The team first mapped which genes are differently regulated in glioblastoma by analyzing publicly available transcriptomic data. They examined publicly available GEO datasets and contrasted tumor samples with non-tumor brain samples to build a disease signature of differentially expressed genes. This analysis yielded more than one thousand genes, with several hundred upregulated and several hundred downregulated. They then conducted functional enrichment to find which biological processes and signaling routes were most involved, including immune signalling and neuronal pathways. The resulting gene list provided the foundation for downstream screening.

From genes to shortlisted medicines

Using the top 45 differentially expressed key genes, the researchers queried the Connectivity Map to find drugs whose expression footprints oppose the glioblastoma pattern. They prioritized compounds with negative connectivity scores because those best suggest reversal of disease-related gene activity. To improve real-world relevance, the team filtered candidates for blood-brain barrier suitability using molecular weight, topological polar surface area, and partition coefficient. They then used network tools to connect predicted drugs with key hub genes and to visualize potential mechanisms. From this pipeline four drugs stood out for bench testing, namely gemfibrozil, doxylamine, valproic acid, and diprophylline.

What went into the lab and what came out

The group evaluated the four drugs in human glioblastoma cell lines using viability assays and complementary imaging and protein readouts. Two candidates emerged as notably more potent, and the other two compounds did not show measurable cytotoxicity and apoptosis within the tested window. Gemfibrozil and doxylamine are the drugs that stood out. They were able to slow down the cancer cells’ growth far better than the commonly used drug temozolomide. 

Cracking the mechanism to making existing treatments more effective

The researchers then explored how these two drugs work inside the cancer cells. They discovered that the drugs disrupted a cleaning process that cells use to stay healthy, called autophagy. When this system was blocked, waste started to build up inside the cells, making it harder for them to survive. At the same time, the drugs triggered an increase in reactive oxygen species, which are unstable molecules that cause stress and damage to cells. Together, these changes pushed the cancer cells toward self-destruction, while normal cells were less affected. An encouraging finding was that these repurposed medicines worked even better when combined with the standard chemotherapy drug temozolomide. In simple terms, they made the cancer cells more sensitive to the treatment that is already in use. This suggests a possible future where existing medicines could be paired to create stronger and more efficient therapies for glioblastoma patients.

Combining Old and New for Better Results

Temozolomide is still the main drug used to treat glioblastoma today. The researchers wanted to identify if the two repurposed drugs could work alongside it rather than replace it. When they combined these medicines with temozolomide, the cancer cells became more vulnerable, meaning that the treatment was more effective compared to using any of the drugs on their own. The team even tested this approach on more complex 3D models of the tumor, which better mimic how cancer grows in the brain, and the results stayed consistent. This opens the door to combination treatments that may make standard care stronger.

What This Means for the Future

The findings give new hope in the fight against glioblastoma. Both gemfibrozil and doxylamine are medicines that can reach the brain, and in lab studies, they managed to weaken cancer cells more effectively than the current standard drug. They also boosted the effects of temozolomide, which means they may be used together rather than as replacements. It is important to note that this research is still at an early stage. The next steps include testing in animal models and further studies on how these drugs affect special cancer stem cells that make tumors hard to treat. If these steps are successful, this approach could speed up the journey of bringing new treatment combinations to patients by using medicines that are already known and approved for other uses.