Glioblastoma multiforme (GBM), the most aggressive tumour of the central nervous system, is highly malignant, resistant to existing drug therapies and associated with high mortality rates.

Overexpression of B-cell lymphoma 6 (BCL6) has been frequently observed in GBM patients, highlighting the urgent need for potent BCL6 inhibitors as a novel treatment strategy.

This research, published in the Genes & Diseases journal by a team from East China Normal University, Kunming Medical University, and Shanghai Yuyao Biotech Co., LTD.

identifies the key role of BCL6 in promoting the proliferation of glioma cells and the progression of glioma.

Initially, the team analysed the data from The Cancer Genome Atlas and Cancer Cell Line Encyclopaedia and revealed that BCL6 is significantly overexpressed in GBM tumours and correlates strongly with poor patient prognosis.

Experiments in GBM cell lines confirmed that silencing BCL6 reduced cell viability and proliferation, while overexpressing BCL6 had the opposite effect—indicating that the survival of GBM cells is highly dependent on BCL6.

To improve the biological activities of BCL6 inhibitors, researchers developed YK01, a novel small-molecule inhibitor that can directly bind to the BCL6-BTB domain and inhibit its biological functions in vitro and in vivo, thus confirming YK01 as a potential compound for the treatment of tumours with high expression of BCL6.

Additionally, MTS experiments demonstrated YK01’s exceptional potency, with nanomolar binding affinity, effectively suppressing BCL6 activity in both cell-based assays and animal models.

Notably, YK01 not only blocked the interaction between BCL6 and its corepressors (SMRT) but also induced degradation of BCL6 protein, reactivating tumour suppressor genes and triggering DNA damage responses.

Importantly, YK01 significantly reduced the growth and invasiveness of GBM cells in vitro and potently suppressed GBM growth in a mouse subcutaneous glioma transplantation model without toxicity.

Furthermore, results revealed that YK01 and the chemotherapy drug temozolomide (TMZ) had synergistic anti-GBM effects, and the combination of YK01 effectively inhibited the in situ tumour growth of GBM and significantly prolonged survival.

In conclusion, this study highlights BCL6 as a promising therapeutic target in GBM and validates YK01 as a potential new treatment strategy.

Given the lack of effective therapies for GBM, this dual approach—targeting BCL6 directly and enhancing the chemotherapy response—could offer real clinical impact.

Source: Compuscript Ltd