Our lab has a strong translational focus aimed at interrogating the molecular basis of disease to achieve therapeutic benefit. Specifically, we are interested in the pathways that dictate cell survival and cell death, namely autophagy and apoptosis. We use a multi-disciplinary approach encompassing biophysical, biochemical and structural approaches to enable an in-depth atomic understanding of protein interactions orchestrating these pathways. This knowledge is subsequently used to design novel ligands targeting the complex machineries governing these processes, engineer mouse models to probe the mechanisms-of-action of proteins regulating the pathways, and develop novel assays based on our understanding of these interactions.
Our research program is aimed at understanding the mechanisms by which proteins regulating cell survival pathways maintain physiological homeostasis and cause disease, and how these pathways can be targeted for disease treatment. We aim to make a genuine impact beyond basic research, in the clinic, with these research findings.
Research areas
Targeting the BCL-2-regulated apoptotic pathway for the treatment of incurable solid cancers
Apoptosis is a genetically programmed form of cell death required for the removal of damaged, redundant or dangerous cells. Resistance to apoptosis is a hallmark of cancer and a critical feature of tumour development and therapeutic resistance. Genetic defects such as gene amplifications that lead to over-expression of the pro-survival members of the BCL-2 family of proteins (BCL-2, BCL-XL, BCL-W, MCL-1 and BFL-1) often give rise to cancer. A new class of drugs, BH3-mimetics, has been developed to trigger apoptosis in cancer cells by antagonising the critical survival factors within the tumour. One such compound is now clinically approved for the treatment of some hematological malignancies in which BCL-2 pro-survival proteins play a well-defined oncogenic role. However, many solid cancers remain resistant to BH3-mimetics monotherapy. We are now investigating how to best unleash the full potential of BH3-mimetic therapy, by using them in combination with standard-of-care chemotherapies or each other, for the treatment of currently incurable solid cancers. All our cancers of interest are characterised by poor survival rates (generally less than a year) and for which new and improved treatment strategies have not been developed for well over a decade.
Understanding the role of autophagy in normal physiology and disease
Autophagy is a catabolic degradation process induced in response to starvation or stress whereby cellular proteins, organelles and cytoplasm are engulfed, digested and recycled to sustain cellular metabolism. As such, it is primarily a cell survival mechanism and its deregulation has been implicated in diseases such as cancer and inflammatory bowel disease (which include Crohn’s disease and ulcerative colitis). We have shown that deletion of a key regulator of autophagy leads to severe disruption to gastrointestinal homeostasis that results in accelerated death. We are now investigating how this regulator mediates intestinal cell survival by autophagy and enables crosstalk with cell death pathways. Work from this study can have important implications on our understanding of IBDs for which there is still no cure.
