Characterising a new target for the treatment of Glioblastoma Multiforme

Olivia Taylor, Joshua Brzozowski, Kathryn Skelding

Background

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumour in humans. The median survival for GBM patients is 10-11 months and has remained static for decades, demonstrating an urgent need to investigate new targets for the treatment of GBM. A potential therapeutic target is brain and acute leukemia cytoplasmic (BAALC) as it is expressed at low levels in normal tissue and is overexpressed in GBM, suggesting that it may be involved in tumourigenesis. The functions of BAALC in GBM have not been examined, however, BAALC plays a role in cell proliferation and survival in leukaemia cells. Novel BAALC inhibitors have been developed that specifically target BAALC, which may provide a more cancer-cell specific treatment, hence, they are important to examine.

Aims

The main aims of this study were to elucidate the cellular functions controlled by BAALC in GBM cells, and to examine the pre-clinical effectiveness of novel BAALC inhibitors in GBM models in vitro and in vivo.

Methods

BAALC expression was altered (siRNA knockdown, overexpression) in GBM cells. Effects on proliferation (resazurin), survival (Annexin) and migration (scratch assay) were measured (n=3). A panel of GBM cell lines were treated with increasing doses of BAALC inhibitors.

Results

We have shown that inhibition of BAALC expression in GBM cells increases cell death, while overexpression increases cell proliferation. Taken together, our data shows that BAALC is involved in controlling GBM proliferation and survival. The BAALC inhibitors kill a range of GBM cell lines in vitro and were shown to be safe and well tolerated in vivo.

Conclusions

There is an urgent need for new strategies for the treatment of GBM. Characterising BAALC, a potential therapeutic target, may provide a more cancer cell specific treatment which may reduce toxicity and side effects, resulting in improvement of patient survival.

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December, 2024

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