New drug therapies to kill Tsc2-deficient cell lines

Scientific Abstract: A key mediator of cell growth in many cancers is through aberrant signal transduction through mammalian target of rapamycin (mTOR). Our laboratory has a long-standing research history on dissecting novel mechanisms of mTOR signalling and relating this to cancer progression and therapy. We recently discovered that clinically approved drugs, nelfinavir and chloroquine, specifically enhanced the levels of endoplasmic reticulum (ER) stress and killed well defined genetic tumour cell models of Tuberous Sclerosis Complex (TSC) with heightened mTOR signalling. This project will lead on from our initial observations through use of the clinically approved proteasome inhibitor. This is a basic research project that utilises TSC tumour cell line models to test the effectiveness of novel anti-cancer drugs that could easily be repositioned to treat Tuberous Sclerosis (TS) patients. This project will determine whether drug combinations with nelfinavir could be effective at treating TS patients as well as cancer patients that have tumours displaying aberrant mTOR signalling and ER stress. Our group is included in the recently funded NISCHR Wales Cancer Research Centre whose central philosophy is to integrate and translate cancer research in Wales, which supports our long-term objective to translate this basic research into the clinical setting.
Significance: A wide spectrum of cancer cells exhibit increased ER stress as a consequence of mTORC1 hyper-activation. By investigating drug combinations that exploit this susceptibility in renal cancer cells and based upon our expertise in mTOR signalling, ER stress and autophagy, we aim to establish the basis for a therapeutic approach that will be readily translatable. Our long-term aim is patient stratification, where the selected drugs and analogues show promise to specifically target tumours with high mTORC1 signalling and ER stress profiles.
Feasibility: The project has been designed so that one aim is not dependant on another, which allows us a level of project flexibility. Many of the materials such as expression vectors, cell lines and PCR primers have already been optimised/characterised through previous research outputs from the Tee lab. The techniques employed in this project are routine for the Tee laboratory, and include tissue culture, shRNA knockdown, cell death assays, flow analysis, western blotting, RT-PCR, molecular biology, and analysis of signalling pathways

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