Grant: Project Grant

Cancer is a devastating disease defined by genetic changes that activate proteins supporting cell growth, or are inhibitory of cell death. Modern oncology aims to specifically target these tumour drivers, which, unlike chemotherapy, has the secondary benefit of leaving normal cells unharmed. Recently, the field has produced a number of specific oncogene inhibitors, yet the results are underwhelming; most targeted therapies show an initial benefit, followed by the development of resistance. To combat resistance, targeted therapies are often combined in multi-drug regimens, though these strategies are biased towards using existing drugs. Our approach aims to first identify new 'helper' drug targets that, upon inhibition, improve the efficacy of first generation targeted therapies. Importantly, we are focusing our screens on cell surface proteins, as they are acutely accessible by antibodies. Experimentally, identifying 'helper' drug targets entails systematically removing each cell surface receptor in isolation from cancer models, then treating these modified cells with a drug. After measuring cell death and proliferation, we can then assess which removed receptor increases drug efficacy. A huge challenge in cancer therapeutics involves surmising whether inhibiting these candidates with drugs can mimic the complete removal of the enzyme, as this is not feasible for treating humans. Our second aim will assess candidate druggability and involves the development of therapeutic antibodies, which are engineered versions of naturally occurring human proteins that can be trained to bind and inhibit cancer targets. Newly designed therapeutic antibodies will be tested for their ability to increase targeted therapy efficacy, hopefully establishing novel approaches for cancer treatment and positively impacting those who suffer from this terrible disease.