Ian Street-projects

Ian Street-projects



Epigenetic mechanisms of acquired tumour resistance

With growing realisation of the importance of epigenetic mechanisms in tumour development and the acquisition of resistance, targeting epigenetic modulators is probably the fastest growing field in drug discovery today.  We have pioneered the development of small molecule inhibitors for two classes of little explored epigenetic modifiers, protein arginine methyl transferases (PRMTs) and histone acetyl transferases (HATs).  Our initial efforts have focused on PRMT5 and KAT6A and we continue to build on these foundations and expand our work to include other members of these important protein families.

Modulators of epithelial mesenchymal plasticity (EMP)

Broadly, we are using two approaches to identify new EMP-targeting drugs.  Today, all new cancer drugs are first tested in patients with advanced metastatic disease this way of testing does not work for EMP-targeting drugs, which are unlikely to reduce the growth of established tumours.  To identify EMP targeting drugs that could be effective for patients at high risk for metastatic breast cancer, we have assembled a ‘library’ of 3,500 “known drugs” and are testing them in functional models of EMP.  We are also using genetic methodoligies to identify new targets for EMP drugs and once validated we will move these targets into drug discovery.

Systematic identification of effective combination therapies

As cancer treatment becomes increasingly personalised, growing emphasis is placed on the development of drugs that target specific mutations and signalling pathways. However, while these drugs are effective in the short term many tumours acquire resistance within a few months. The fundamental problem is that advanced cancers are genetically heterogeneous, and small populations of cells within each tumour survive treatment and continue to grow.  Combinations of drugs targeting different cancer pathways may offer lasting remission. We are working with the Sieber lab developing novel methodologies to identify and assess the effectiveness of combination therapies in colorectal cancers.