Nov 04: Cancer remains among the most deadly diseases worldwide. Globally, more than 300,000 new cases of brain cancer are reported each year, with glioblastoma, an aggressive form of brain cancer, accounting for over 250,000 deaths. The current standard-of-care involves the use of temozolomide, a chemotherapy medication. However, the tumour can be difficult to control because cancer cells evolve to evade the effects of such treatments. Thus, finding new ways to target these cells is an important area in cancer research.

Research from the Indian Institute of Technology Gandhinagar explores one such possibility of tackling the drug-resistant glioblastoma. It highlights two promising candidates that can target tyrosine threonine kinase, which is integral to cell division. High levels of this protein have been linked to glioblastoma progression. The results have been published in the Journal of Biological Chemistry and RSC Medicinal Chemistry. 

Interrupting the Quality Control Inspector! 

Biological cells have tightly regulated systems for distributing genetic material. TTK helps manage one of the checkpoints, and its job is to ensure that chromosomes are properly handled as a cell divides. Upon spotting a mistake during cell division, TTK triggers a safety alarm that causes the process to pause while the repair takes place. Once everything is in the right place, TTK gives the green light, and the cell divides successfully.

Since cancer cells divide at a much faster rate than normal cells, they rely heavily on TTK to survive their chaotic division cycles. The researchers asked whether disrupting this checkpoint could make it harder for glioblastoma cells to manage the damage to their DNA. It can reduce their viability and enhance their sensitivity to treatments like radiotherapy. 

Gaurav Rai said,

“Earlier studies have linked TTK’s involvement in resistance to TMZ, a commonly used chemotherapy drug. We wanted to explore whether modifying a candidate from one of our previous studies, J54 (a selective inhibitor of TTK), could help us target TTK more effectively and guide further research into ways of tackling drug-resistant glioblastoma.” The first author of this study, Gaurav, is a PhD student in the Chemistry Department at IITGN and the recipient of the Prime Minister’s Research Fellowship. 

The Chosen Ones 

Laboratory experiments revealed that SPK17 stood out among more than 10 compounds developed by the researchers in one part of the study. Compared to TMZ, the SPK17 concentration associated with a 50% reduction in the glioblastoma cell viability was approximately 176 times lower for LN229 cells and 85 times lower for U87MG cells, which are two human glioblastoma cell lines. What was more interesting was that SPK17 produced approximately eight times the cell-death signal when tested at 10 micromolar, compared with 200 micromolar TMZ in the case of glioblastoma cells that had become resistant to TMZ under experimental conditions.

SPK17b was the most prominent among the five compounds in the other part of the study. Compared to TMZ, the IC50 for SPK17b was approximately 81 times lower for LN229 cells and 59 times lower for U87MG cells. Further, SPK17b’s concentration was at least 59 times lower for producing the cell-death signal in the case of LN229-TMZ-R cells when tested at 10 micromolar, compared with 200 micromolar TMZ. 

In other words, less SPK17 and SPK17b were needed to kill 50% brain cancer cells compared to the routine chemotherapeutic drug, suggesting a promising lead. 

Second author of the other study, Deepika, added,

 “We also realised that SPK17b appeared to do more than slow the growth of glioblastoma cells. The treated cells showed an impaired ability to metastasise or spread, one of the hallmarks of cancer.” Deepika is also a PhD student in the Chemistry Department at IITGN. Together, these results suggest that the two compounds may interfere with several processes that help tumour cells survive and multiply.

Sharing his thoughts on the mechanism involved, Gaurav explained,

“Both compounds act on the same protein, TTK, but the two studies followed different consequences of blocking it. SPK17 removes a built-in pause that normally gives a dividing cell time to mend its damaged DNA. The cell is pushed through division with the damage unrepaired, and it accumulates until the cell dies. SPK17b instead causes a build-up of reactive oxygen species, toxic by-products of the cell’s own metabolism, until the cell’s defences are overwhelmed and it self-destructs, while also leaving surviving cells less able to move and invade surrounding tissue.”

The Road Ahead 

Drug discovery should be viewed as a journey with several checkpoints of its own. A compound must first show that it can affect the intended biological target. The next step should be to establish whether the candidate is effective in progressively complex biological systems and whether its benefits outweigh its risks. 

According to Prof Sivapriya Kirubakaran,

 “When you are working on a disease as aggressive as glioblastoma, you are aware of how urgently better treatment options are needed. Findings like those from our study can bring us closer to asking the right questions to improve understanding of difficult diseases. Our two compounds give us a mechanism-based therapeutic strategy to investigate how we might target drug-resistant tumour cells. Future studies to understand the efficacy of the molecules in animal studies are ongoing.” Professor Kirubakaran is the Kankuben Bakshirambhai Gelot Chair Professor in the Chemistry Department at IITGN and heads the Cancer Chemical Biology lab at the Institute.

The findings of this study align with aspects of United Nations Sustainable Development Goal 3 (3.B), which supports research and development of medicines for non-communicable diseases. In India, it is also in alignment with the efforts to strengthen cancer care under the National Programme for Prevention and Control of Non-Communicable Diseases.