Mutations or amplification of many oncogenes, such as Ras and Myc, have been known for up to 40 years to be drivers of many different cancers. Yet, effective ways of targeting these for inhibition with small molecules still do not exist. Consequently, together with several other oncogenes, these are often referred to as ‘undruggable’ targets. Targeted degradation of such oncogenes has the potential to make them ‘druggable’ targets and potentially lead to therapeutics. Recently, several strategies have been developed to selectively target the degradation endogenous proteins. The Sapkota laboratory has developed Affinity-directed PROtein Missile (AdPROM) system that uses nanobodies/monobodies to target endogenous proteins for recruitment to the ubiquitin-proteasome machinery for their degradation (1,2). AdPROM, when combined with CRISPR/Cas9 to introduce a targeting moiety on the oncogene of interest, allows one to rapidly assess whether it can be targeted for ubiquitin-mediated degradation and its degradation reverses oncogeneic phenotype. This information can then be translated into developing cell-permeable PROteolysis TArgeting Chimeras (PROTACs) to induce achieve targeted degradation of the specific oncogenes. The Ciulli laboratory has developed several PROTACs, which are small heterobifunctional molecules that bring together a target protein and an E3 ligase together for ubiquitin-mediated destruction of the target protein, against specific proteins (3). This project aims to combine cutting-edge, multidisciplinary techniques in AdPROM, CRISPR/Cas9 gene editing, cell and molecular biology, proteomics, signaling to establish whether some of the ‘undruggable’ oncogenes can be destroyed by proteolysis and potentially utilise this information to develop PROTACs against validated targets. The Sapkota and Ciulli labs, and their collaboration with leading pharmaceutical industry through the Division of Signal Transduction Therapy, are well-equipped to train the prospective student in all of these areas.
1. Fulcher, L. J., Macartney, T., Bozatzi, P., et al. (2016). Open Biol 6
2. Fulcher, L. J., Hutchinson, L. D., Macartney, T. J., et al. (2017). Open Biol 7
3. Hughes, S.J. & Ciulli A. (2018) Essays Biochem 61(5):505-516