Osteosarcoma patients are treated before and after surgery with a chemotherapy combination named MAP which comprises high-dose methotrexate, doxorubicin and cisplatin.
Methotrexate is absorbed throughout the body and very high doses are required to ensure enough of it reaches the tumour. Because the drug cannot differentiate between the cancerous and normal cells, it results in very severe toxicity. As a result, methotrexate doses frequently need to be reduced, and occasionally abandoned altogether, which has obvious repercussions on the outcomes for patients.
In 2018 , we funded a PhD studentship to investigate the possibility of creating a chemically modified methotrexate, which would remain inactive while distributed throughout the body, becoming active only in the tumour. This approach is known as a 'prodrug'.
Matrix metalloproteinases, or MMPs, are enzymes that cleave amino acid chains that form proteins. A particular MMP, MT1-MMP is found in very high levels in osteosarcoma cells compared to normal cells, which provides an excellent way to target the cancer cells.
The research team planned to “hide” methotrexate among an amino acid chain that could be broken by these enzymes, allowing for the drug to be “freed” only at its intended destination – the tumour – thereby reducing the toxic effects it has on normal cells. It also hoped to increase its ability to kill osteosarcoma cancer cells, as it would be delivered precisely where is needed.
PhD student Hannah Spencer has shown that it is possible to prepare these MMP activated methotrexate prodrugs and that they can be differentially activated in tumours, compared to other tissues like liver, or kidney in the laboratory.
What does the next phase of the project aim to achieve?
The next phase of the project will now concentrate on the optimisation of the best of the prodrugs prepared and to study their behaviour in more advanced laboratory models of disease. The team will look at whether the prodrugs are effective at reducing osteosarcoma growth and metastasis and will look at whether these are less toxic than the parent methotrexate drug. This project will look to select the best candidates to take forward to further pre-clinical research.