The recent discovery of mutations in the PIK3CA gene found in many human tumours and the demonstration of oncogenic activity by the PI3 kinase enzyme that the gene encodes, provides for a novel and potentially highly specific method of treating many cancers.
A drug that can block this mutated enzyme's activity without interacting with the normal forms of the enzyme may be a "magic bullet" therapeutic. However, achieving such a drug may be extraordinarily difficult as the differences between mutant and normal forms of the enzyme are very subtle.
In this project we plan to develop a model experimental system to assess the anti-cancer potential of a mutation specific PI3 kinase inhibitor. In short we plan to engineer a magic bullet experimental system. By engineering a second mutation in the enzyme, we can make it exquisitely sensitive to an inhibitor, specifically designed to fit that mutation.
The inhibitor will also be inactive against the normal forms of the enzyme. This doubly mutated enzyme can be expressed into cells, inducing oncogenic transformation and other cancer-related activities that can only be blocked by the specific inhibitor.
The system will allow direct observation of activities due to the mutated isoform, and the consequences of its inhibition upon tumour growth. This provides for a validation of the PI3 kinase magic bullet hypothesis, but also as non specific inhibitors of the enzyme will also be trialled as anti-cancer agents, this system will also provide a comparative indicator of whether systemic effects of these agents are due to non-selectivity.
Dr Philip Thompson, Professor Bert Vogelstein
Research Grant: 2007-2009
$66,750 per annum