Area of research:
Project aims and objectives:
Our research is focussed on understanding the mechanisms that lead to therapy failure in prostate cancer and how these can be targeted to prevent cancer deaths. One way prostate cancers become resistant is by reprogramming their metabolism to overcome metabolic stress induced by treatment. We aim to identify drugs that can target metabolic networks that are unique to cancer cells.
Previous work in our lab has identified a compound, BD, isolated from a sea squirt on the Great Barrier Reef, to have potent effects on cancer cell viability, cell cycle and cancer cell metabolism in a some cancer cells that become addicted to a certain metabolism. Based on our observations we hypothesise that BD is targeting an important component of the glycolysis pathway.
The mechanism of action (MOA) of BD as it relates to PCa metabolism has not been fully characterized. Therefore, these studies aim to define the effect of BD on glycolysis using in vitro models of advanced PCa. This will help identify which metabolic changes make the subset of prostate cancer cells sensitive to BD.
Project methodology and resources:
Studies will examine the effects of BD on glycolysis and lactate. These data will be evaluated to determine the effect of BD on glycolysis and branchpoint biosynthetic pathways.
The BD effect on lactate efflux will be examined by directly measuring intracellular lactate content and efflux using direct lactate measurement (Sigma kit available in the lab) and energy flux technology using the Seahorse platform (Reagents and consumables available).
BD effects on lactate efflux will be further determined by examining the additional or independent effects on MCT1 inhibitors (BAY002, experimental conditions established and drug available in the lab).
Expression levels of the protein that produces lactate (lactate dehydrogenase) will be determined in BD sensitive and insensitive cell lines (previously characterised and based on existing RNAseq observations).
Effect of BD on LDH expression will be tested in combination and independent of LDH inhibitors (e.g. galloflavin, experimental conditions established).
Finally, studies will inhibit OXPHOS, to determine whether forcing increased lactate synthesis causes synthetic lethality (e.g. using OXPHOS inhibitors such as metformin, etc) to force the cells to depend on glycolysis.
Location of research:
Translational Research Institute (TRI)
Some knowledge of biochemistry and cell biology will be beneficial. Students will be taught tissue culture skills, relevant biochemical analytical assays and data analysis. Laboratory techniques such as pipetting and aseptic technique will be useful.
Students will work closely with researchers on laboratory tasks until adequate competency and confidence is achieved. Researchers and supervisors will be available daily. Desk space at TRI will be arranged which includes IT resources.
Literature review; laboratory experiments; data collection; data analysis.
Contact the supervisor for more information.