The cytosolic isoform BCAT1 has recently been implied to support growth of ERa-negative breast cancer (1), as well as promote resistance to bevacizumab in glioblastoma (aggressive brain cancer) (2). Further, BCAT1 inhibition is associated with increased sensitivity to CDDP treatment in prostate cancer (3), and BCAT1 is also upregulated in gastric cancer (4).
In a previous project, we have identified several BCAT1 and BCAT2 inhibitors, and given the above listed roles of BCAT in various pathological disorders, it is of interest to identify and develop inhibitors to be used in treatment of cancer. We have already a small in-house panel of inhibitors and aim to expand this set of compounds and develop even more potent molecules.
As a cancer model in this project, we focus on glioblastoma multiforme (GBM). GBM is the most prevalent and aggressive malignant tumor of the central nervous system. With the current available treatment, the median overall survival of glioblastoma patients is just over a year, a dismal fact that has not changed over many decades. Despite many attempts to find therapeutic strategies, there are currently very few drugs approved to treat glioma patients and therefore, there is a great interest in finding new inhibitors which can inhibit proliferation of glioma cells. We have a range of clinically relevant mouse and human glioma cell lines grown in serum-free medium, which capture the breadth of heterogeneity in glioma patients, which will be used to test whether these inhibitors can inhibit gliomas.
Aim of project
The aim of this project is to analyse present in-house BCAT1/2 inhibitors in a cell-based assay with a GBM model, and search for new compounds with even higher potency than our current set of compounds. This will be achieved using cell based assays whereby cancer cells are exposed to the drug candidates. We will also test for any adjuvance (increased effects) of current drugs in combination with the BCAT inhibitors.
Project plan and methods
The project will consist of the following tasks and methods
- Develop a plate-based, cancer cell screening setup to test our current panel of inhibitors against different GBM cell lines.
- Use the developed setup to determine general toxicity and cancer cell specific toxicity.
For the inhibitors which specifically inhibit glioma cells, perform transcriptomic (RNA-seq)