Cancer Cell Cycle
An underpinning theme of our studies is that we believe, in order to design better therapies that effectively treat cancer, it is essential to decipher the molecular and biological details of pathways that control proliferation in normal cells and thereafter understand how they become aberrant in cancer.
A hallmark of tumour cells is evident in the control of the G1 to S phase transition; in normal cells this transition is tightly regulated whereas tumour cells progress liberally into S phase in an unrestrained fashion. There are two key pathways of pivotal importance that govern progress through G1 into S phase, controlled by the retinoblastoma tumour suppressor protein pRb and the p53 tumour suppressor protein. pRb principally acts as a transcriptional regulator of the E2F family of cell cycle regulating transcription factors. In contrast, p53 is a stress-responsive transcription factor that activates genes involved with cell cycle arrest and apoptosis. Most tumour cells harbour mutations that alter pRb and p53 activity. Loss of pRb results in deregulated proliferation as a consequence of liberating E2F activity, whereas loss of p53 causes an insensitivity to checkpoint control.
The primary objective of our work is to explore the regulation of and control by pRb and p53 activity. Specifically, we have defined new levels of control in regulating pRb tumour suppressor activity, particularly novel post-translational signals. We have elucidated new members of the E2F family, and identified the key pathways through which they act. Functional characterisation of E2F in cell cycle control and apoptosis has identified a remarkable level of complexity that governs the switch to apoptosis. Our p53 research is principally focused on uncovering the diverse modifications that dictate the outcomes of the p53 response to stress.
We believe that biological knowledge on the mechanisms which drive cancer cell proliferation can be harnessed in designing new therapeutic modalities to treat cancer. Consequently, we work closely with the bio-technology and pharmaceutical sectors, together with clinical colleagues in translating our academic discoveries into an applied clinical setting. Drugs emanating from our earlier studies have been approved for haematological malignancy.
A major focus of our current work is to develop technologies that enable predictive biomarkers to be identified for cancer therapies. We have devised a genome-wide loss-of-function screen that identifies predictive biomarkers and deployed the platform to develop companion diagnostic tests for diverse cancer drugs.