Melanoma is a devastating form of skin cancer caused by uncontrolled growth of skin pigment cells, and is the leading cause of death from any skin disease. Once the melanoma has started to spread throughout the body in a process known as metastasis, then prognosis is poor and at this stage the survival rate falls dramatically to less than 15%. Identifying new molecular targets for therapeutic intervention is of paramount importance. Recently, we made an important breakthrough and discovered a 'rogue enzyme' that causes the destruction of a natural inhibitory protein normally responsible for preventing melanoma cell metastasis (Soond and Chantry, Oncogene, 2011; Chantry, Cell Cycle, 2011). This protein is Smad7, and the 'rogue enzyme' is a Ubiquitin Ligase known as WWP2. Furthermore, in a recent BSF-funded Small Grant project we have now identified a small cell permeable peptide (Pep-WW4) that blocks the specific action of WWP2 on Smad7, and thereby prevents cellular processes associated with melanoma progression. The goal of this PhD project is to now further refine and optomise Pep-WW4 and identify minimal sequence elements required for activity, and to also develop other novel groups of drugs that block WWP2 enzyme activity. The overarching strategy will be to boost inhibitory Smad7 levels and halt melanoma spread. Our approach will involve state-of-the-art cancer cell/molecular technologies encompassing structure-based design and high-throughput screening. The project provides an excellent training platform for a PhD student to gain a wide-range of multidisciplinary skills relevant to the study of a major skin disease, and could lead to the development of new treatments to improve patient survival in malignant melanoma.

Soond, S., and Chantry, A. (2011) Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFbeta signalling and EMT, Oncogene, 30, 2451-2462.

Chantry, A (2011) WWP2 ubiquitin ligase and its isoforms: New biological insight and promising disease targets. Cell Cycle, 10(15): 2437-2439.

Soond, S., and Chantry, A. (2011) How ubiquitination regulates the TGFbeta signalling pathway: New insights and new players. Bioessays, 33(10): 749-758.

Cutts, A., Soond, S., Powell, S., and Chantry, A. (2011) Early phase TGFbeta receptor signalling dynamics stabilised by the deubiquitinase UCH37 promotes cell migratory responses, International Journal of Biochemistry and Cell Biology, 43, 604-612.