Dr David Mann
Imperial College London
Sarcoma UK is investing in research leaders of the future. Our PhD programme aims to start a researcher’s career in sarcoma by funding a training fellowship which focuses on a hypothesis-driven research project.
This exciting PhD project builds on preliminary work by this team identifying fragments of drugs which prevent cancer growth. These pieces will now be developed into chemicals that will form the basis of new drugs for the treatment of sarcoma.
Selective irreversible allosteric inhibition of MCL-1 to potentiate apoptosis in sarcomas
Cancer cells develop multiple mechanisms to escape the normal controls that exist to stop excessive cell division. One of these mechanisms involves increased production of proteins that prevent cell death, thus making it harder to kill cancer cells. One of the key proteins whose overproduction stops cells from dying is called Mcl1. It does this by inhibiting the activity of the proteins that can trigger cell death. This is true in many cancers and particularly in a range of sarcomas (rhabdomyosarcoma, osteosarcoma, Ewing’s sarcoma, GIST, etc).
This project involves developing small molecule chemicals to inhibit the function of Mcl1 and thereby re-instate the sensitivity of cancer cells to death. Preliminary work by this team has identified drug fragments (i.e. parts of drugs) that selectively bind to Mcl1 and which the group will now develop into chemicals with more drug-like properties during the course of the PhD. The compounds being developed act by binding to Mcl1 irreversibly and hence have a potent effect on tumour cells. It is predicted that the combination of Mcl1 inhibitors with other chemotherapeutic agents that promote death will give very strong and robust responses leading to selective killing of sarcoma cells.