Cancers known as sarcomas form in tissues such as muscle, fat, nerves and tendons that connect, support and surround the body’s organs and bones. There are currently very poor survival rates for people diagnosed with this form of cancer.
Cells have an inbuilt mechanism, the telomeres, that determine how many times the cell can replicate. Telomeres shorten each time the cell divides to reproduce itself – eventually reaching a critically short length that prevents further division.
Cancer cells evade this normal process by finding ways to extend their telomeres. Sarcomas and other cancers use a mechanism called “ALT”, in which DNA is added to the end of the telomere by copying it from somewhere else. The ALT process is active in 45 to 60% of sarcoma tumours.
Treatment options for patients with sarcoma have not changed in the past 35 years, in part because no suitable ALT specific drug target has been identified.
Dr Rohan Bythell-Douglas and his colleagues have identified a key weakness in the ALT pathway. Targeting this weakness not only stops telomeres from being extended, it specifically and quickly kills the cancer cells.
The team has also identified drug fragments that target the ALT weakness. While these drug fragments don’t yet present a treatment option, Rohan’s project will use X-ray crystallography to see how the fragments could be modified to improve their effect.
“We aim to build an informed strategy for modifying the drug fragments into more mature drug-like molecules, with the goal of developing a drug which could be used in the clinic to treat sarcomas,” says Rohan.
Dr Rohan Bythell-Douglas
Rohan is an expert in the biochemistry and structural biology of DNA repair enzymes involved in cancer and rare genetic diseases. His goal is to uncover the key mechanistic details of DNA damage repair, down to the resolution of individual amino acids. This level of detail helps Rohan and his colleagues understand how genetic mutations in individual people can increase their risk of disease, and supports the design of new drug treatments.
Rohan’s Rising Star project brings together the components of his research career to date: biochemistry, structural biology and digital protein modelling.