One of the biggest challenges in our fight against cancer stems from the fact that because cancer cells originate from normal cells in the body, they still maintain many of the features of normal cells. Drugs we use in the clinic to kill cancer cells also affect normal cells, which is the reason for the side effects patients experience. However, cancer cells are not quite the same as normal cells, and we can take advantage of their differences to target them.
Ewing sarcoma cells carry a protein on their surface named CD99 (cluster of differentiation 99 glycoprotein) that identifies them. We know that when CD99 is artificially removed from Ewing sarcoma cells, they are much less capable to develop tumours and metastasise.
Therefore, inhibiting CD99 presents itself as a very attractive treatment option. However, to date, there are no drugs that can successfully inhibit CD99 on Ewing sarcoma cells.
Our first International Explorer Grant was awarded to Professor Aykut Üren from Georgetown University in Washington, DC, USA, to investigate if drugs that are able to interact with CD99, could be developed as a novel treatment for Ewing sarcoma with reduced side effects.
What were the aims of this research project?
Professor Üren and his research group have discovered that an existing drug, clofarabine, which is already used to treat children with acute lymphoblastic leukaemia, directly binds to CD99 and inhibits its activity. The drug kills Ewing sarcoma cells with great selectivity. However, clofarabine, when used in leukaemia patients, shows severe side effects, which are due to its ability to inhibit DNA synthesis in normal cells, a process that takes place inside the cell.
The project aimed to design, prepare and test clofarabine derivatives that can still bind to the CD99 on the cell surface, but cannot enter the cell, therefore, are unable to inhibit DNA synthesis. The idea is that these compounds will still be able to recognise and kill Ewing sarcoma cells, but will have much weaker side effects.
Results of this study:
They created created 26 new compounds and evaluated them in different experimental models. Two of these compounds showed very promising results and selectively killed Ewing sarcoma cells in a petri dish. Based on their new structure and the way they were killing Ewing sarcoma cells, They predict that the new compounds will have fewer side effects in patients. The next step in the study would be to investigate these drugs in more advanced laboratory models to validate if they indeed are less toxic or not.
Their results have been published in the scientific literature and can be accessed here.
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