Structure and function of genes that regulate tumour phenotypes
Multiple cellular pathways are deregulated in tumours, some of which alter growth and the propensity for tumour cells to invade and spread to other sites. Our group focuses on two imprinted genes frequently disrupted in cancer, IGF2 ligand and IGF2 receptor (IGF2R). We have studied the structural basis of the evolution of binding of the IGF2 ligand to the receptor and are exploiting our knowledge of the ligand/receptor interaction to develop domain 11 of IGF2R as a soluble ligand trap for IGF2.
We have characterised IGF2 function in a number of mouse models of tumorigenesis. Our work indicates that IGF2 acts as a progression factor during the early stages of tumour formation. Thus targeting IGF2 may, in some instances, be beneficial to control the growth of tumours. A potential application of an anti-IGF2 therapeutic is for cancers that over-express IGF2 and are functionally dependent on the ligand. One aim of our work over the next five years is to test this in a human clinical trial.
Projects have also been developed to investigate genes commonly disrupted in carcinoma rather than early stage cancers - targeting these pathways may be more effective for prevention than trying to tackle the tumours once fully established. Aside from IGF2, these genes include E-cadherin (Cdh1) and Smad4 in intestinal tumours, as well as novel genes and translocations specific to a large group of rare tumours derived from mesenchyme, called sarcomas. In Ewing sarcoma for example, inhibition of the IGF pathway has been associated with some remarkable responses to treatment. Investigation of these observations is underway in a joint bench and bedside programme that incorporates a biomarker and response endpoint Phase II trial with anti-IGF pathway agents.
The team’s expertise ranges from molecular biology and statistics through to early phase clinical trials, our integrated and vibrant team spans bench to bedside, basic and translational research.
Oncotarget 7(43): 69883-69902.
PNAS 113(20): E2766-75.
PlosOne in press 9: e107105. doi: 10.1371/journal.pone.0107105. eCollection.
Science 338: 1209-13.