Developing a new drug for the treatment of ALT-positive cancers

The challenge

Chromosomes contain repetitive regions of DNA called ‘telomeres’, which protect the ends of a cell’s DNA during cell division. As cells divide, telomeres naturally get shorter - this eventually erodes vital DNA and kills cells if they divide too much. This means that to keep growing, cancers must develop a way to lengthen and maintain their telomeres. Some cancers do this through the 'Alternative Lengthening of Telomeres' (ALT) pathway. 

The ALT-pathway is common in certain cancers affecting children and young adults, like brain cancers, bone cancers, and other cancers like neuroblastoma. ALT-positive cancers have very low survival rates, but there are no targeted treatments that can fight ALT in cancer cells yet.

The project

Dr Jon Elkins and Dr Anna Rose at the University of Oxford hope to develop a new drug which will specifically target ALT-positive cancer cells. Their teams’ research has shown that the ALT pathway relies on maintaining a certain level of DNA damage. They therefore believe that increasing DNA damage and forcing the ALT-pathway into overdrive could kill ALT-positive cancer cells.

The researchers have identified an enzyme that repairs certain types of DNA damage in cancer cells, but that is not essential in healthy cells. In this project, they aim to develop a new drug to block the action of this enzyme, leading to increased levels of DNA damage in ALT-positive cancer cells. Dr Elkins’ team will test thousands of chemicals to identify which can efficiently block the enzyme’s activity. Finally, Dr Rose’s team will test the most effective options in various ALT-positive brain and bone cancer cells, alone or in combination with current DNA-damaging drugs.

The impact

The hope is that, if the enzyme is blocked from repairing cancer cell DNA, there will be an accumulation of damage that leads to rapid cell death. In early research, the team observed much lower levels of damage in normal cells, so they are hopeful that targeting this enzyme would be minimally toxic to non-cancerous cells. In addition to testing any new drugs alone, the researchers have evidence to suggest that this method would make standard chemotherapies more effective. Together, this project could provide a vital new weapon against ALT-positive cancers that could improve survival for these young patients.