A chemical biology approach to the study of amoeboid invasion by tumour cells

Cancers kill because they are able to migrate around the body and invade other organs, growing there and causing the organ to fail. One way they do this is by producing enzymes that are able to cut through the matix of the body and allow the tumour cells to force their way in. These enzymes represent a potential drug target, but so far, no candidate has made it into the clinic. One reason for this may be that the cells are able to change the way they invade. Instead of using brute force to cut their way into the matrix, the cells are able to alter their shape and squeeze their way into the matrix, moving like the single celled organism known as an amoeba. This amoeboid invasion is still under very preliminary study but a natural product, isolated from a marine sponge and called a neopetrosiamde, has been shown to inhibit this effect. Using the natural product as a tool may help us to identify processes involved in amoeboid invasion and we intend to make this and study its effects in biological systems. We will also make analogues, with single changes to the structure, to identify the requirements for inhibition and ultimately to design new therapeutic agents.

The mechanisms by which tumour cells are able to metastasise and to establish new tumours at secondary sites are key therapeutic targets in the development of new treatments for cancer. Mesenchymal invasion, in which matrix metalloproteinases (MMPs) cleave the the matrix to allow cells to invade, has been the focus of a large number of studies. More recently, attention has also been drawn to a secondary mode of invasion that may be a form of resistance to drugs targeting MMPs. This has been referred to as amoeboid invasion. In this proposal, we intend to use a chemical biology approach to study amoeboid invasion utilising the recently described natural products the neopetrosiamides. These are the first natural products described to inhibit amoeboid invasion and as such can serve both chemical tools and also as lead compounds for the development of novel therapeutics. The specific aims of this proposal are to synthesise the neotpetrosiamides by solid phase methods, along with smaller fragments to establish a structure activity relationship, to study the effects of the compounds on cell adhesion, cell migration in two dimensions and cell invasion in three dimensions and also to use live imaging to study effects on the actin cytoskeleton. These studies will then feed back into further rounds of synthesis to idea the minimum structures required for biological activity and help in the design of small molecules targeting amoeboid migration.