STORY CREDITS
Writer: Vanajakshi B.H.
Photo: Arijit Reeves
Researchers at the IIT Gandhinagar have unveiled a novel approach to enhance glioblastoma treatment. Glioblastoma multiforme (GBM) is a particularly aggressive brain tumour with limited treatment options and poor prognosis. Standard therapies like Temozolomide (TMZ) offer minimal survival benefits, primarily due to the tumour’s ability to activate DNA repair mechanisms that counteract TMZ’s effects. This challenge underscores the urgent need for innovative treatment strategies.
IITGN’s latest study focuses on phenothiazine-based Tousled-Like Kinase 1(TLK1) inhibitors, specifically designed to target this overexpressed kinase in GBM. TLK1 plays a critical role in DNA repair, which is often overactive in GBM cells, making it a prime target for new treatments. The team has identified J54, a phenothiazine compound, as a particularly promising candidate with significant cytotoxic effects against GBM cells.
The study highlights that combining J54 with TMZ disrupts DNA repair processes more effectively than either treatment alone. This combination enhances the cytotoxic impact on GBM cells by causing sustained DNA damage, which the cancer cells struggle to repair. This approach shows considerable promise, especially for GBM cells deficient in O6-methylguanine-DNA methyltransferase (MGMT), an enzyme that contributes to TMZ resistance. The combination of J54 and TMZ has led to a marked reduction in clonogenic growth and inhibition of cell migration and invasion, crucial factors in the aggressiveness of GBM.
In addition, the research demonstrates that phenothiazine-based TLK1 inhibitors alone can also effectively reduce clonogenic growth and limit cell migration and invasion in MGMT- proficient GBM cells. This suggests that J54 and similar compounds could serve as effective standalone treatments where TMZ alone is insufficient.
The study further reveals that J54, when combined with TMZ, leads to a synergistic increase in γH2AX levels, a marker of DNA damage, indicating that this combination impairs DNA repair mechanisms and enhances cytotoxicity. The findings point towards a significant potential for phenothiazine-based TLK1 inhibitors in developing more effective GBM therapies.
Prof Sivapriya Kirubakaran stated, “Through our comprehensive study of the proteins involved in glioblastoma and the strategic design of specific small molecules, we are confident that we will soon have a promising therapy for this devastating disease.”
The research team at IIT Gandhinagar, comprising an all-women group, including Prof Sivapriya Kirubakaran from the Department of Chemistry, Banu Priya, a PhD scholar and now Research Associate, Dimple Chhabria, a Senior JRF and Project Associate, and Janhvi Dhongadi, presents a unique perspective on targeting TLK1 to overcome GBM’s resistance to conventional treatments. Their innovative approach deepens our understanding of GBM
therapy and opens new avenues for combination treatment strategies. However, further preclinical studies are essential to validate these findings and assess the safety and efficacy of these compounds in more complex biological environments.
The progress made by IITGN represents a crucial step forward in the quest for innovative glioblastoma therapies, offering new hope for patients battling this challenging and often fatal disease.
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