Treatment resistance drives the search for novel targets and inhibitors, with cancer cell metabolism currently experiencing an unprecedented interest in drug discovery. Prostate cancer (PCa) cells show increased lipid uptake and de novo lipogenesis along with auxiliary pathways such as the pentose phosphate pathway, glutaminolysis and β-fatty acid oxidation, which are critical for PCa growth and survival. The search for new agents from nature that target metabolic vulnerabilities of PCa is challenged by the high discovery rate of compounds that inhibit classical targets (e.g. microtubule dynamics). We have integrated multiple assays using commercial sensor reagents and designed a first-in-kind screening platform using high-content imaging to measure critical parameters of PCa lipid metabolism, oxidative stress and mitochondrial status. We will apply this platform to screen a 472-membered library of pure natural products from extracts of Australian biota (including plants, fungi and marine invertebrates). We will also profile numerous commercial metabolic inhibitors with known targets by our proposed assays which will facilitate compound categorisation and selection for validation mechanism of action studies. As proof-of-principle, three natural products from the compound library were subjected to the proposed multiplex analysis of lipid flux and mitochondrial status, which detected enhanced fatty acid uptake, increased number and mass of lipid droplets/cell, decreased mitochondrial activity and number of mitochondria with unchanged mass/cell (mitochondrial fusion).
This poster aims to present the concept of this first-in-kind PCa metabolism-tailored screening platform that will select for and expedite the identification of novel metabolic inhibitors from nature.