The most common primary bone cancer in children and young adults, osteosarcoma, is a highly malignant bone tumour which affects both children and adults. A common chemotherapy drug, high-dose Methotrexate is administered with other chemotherapy drugs as a combination regimen to treat osteosarcoma.
Because Methotrexate is absorbed throughout the human body, very high doses are currently required to ensure enough of the Methotrexate reaches the target osteosarcoma tumour cells. It is nonspecific in its application; meaning Methotrexate cannot distinguish between cancerous and normal cells. As a consequence, the high dose Methotrexate does not only target cancerous cells, they target normal cells. This leads to significant side effects, including but not limited to; low blood counts, hair loss, mouth sores/ ulcers, nausea and diarrhoea.
As well as patients needing certain fluids for the Methotrexate to stay dissolved in the body during treatment, high dose Methotrexate is highly toxic and requires complex medical monitoring and a special fluid called ‘leucovorin’ which helps reduce the side effects on normal body cells.
What was this project aiming to achieve?
Dr Robert Falconer and his team at the University of Bradford aimed to create a chemically modified methotrexate ('prodrug'). This prodrug treatment combats the challenges of treatment by reducing the side effects it has on normal cells, as well as hopefully increasing its ability to kill osteosarcoma cancer cells.
How will Dr Falconer’s research achieve this?
The research team have found a way of selectively activating the chemically modified Methotrexate so its effects are localised to the osteosarcoma tumour cell microenvironment, with no active application to normal tissues. Therefore, when this chemically modified Methotrexate is administered into the bloodstream it is inactive and will not affect any of the body’s normal healthy tissues. Potentially, this means a dramatic reduction in side effects in comparison to the currently administered Methotrexate.
Matrix metalloproteinases, or MMPs, are enzymes which cancer cells possess but normal cells do not. MMPs are known to be involved with behaviours associated with malignant activity such as cell proliferation. MMPs are found in high quantities in osteosarcoma tumour cells so they are perfect for triggering the activation of the modified Methotrexate. Ultimately, these MMPs will activate the Methotrexate when it arrives into the microenvironment of the tumour, thus enabling a specific, efficient and localised arsenal on the osteosarcoma tumour cells.
Results of the study:
Through a series of lab experiments, PhD Hannah Spencer synthesised a library of 31 new methotrexate ‘prodrugs’. These prodrugs were modified versions of methotrexate which mean that the drug is only activated once inside the tumour. Each compound was tested in the lab to see how effectively it is activated in tumour tissues, and at the same time how stable it is (to see how much active drug is released) in normal healthy tissues. They narrowed down the drugs to a shortlist of 4, and tested how well these drugs behaved in an animal model. The team then selected the best compound for detailed testing. The best compound was then tested in a mouse model of cancer. They were able to show that the active drug was successfully released in the tumour where needed, and that we reduced the amount of active drug seen in normal healthy tissues. 15 times less drug was seen in the liver, while 10 times less was seen in blood. Reduced drug concentrations (2-fold) were seen in kidneys, where the drug is excreted. They want to improve on this further in our next generation of compounds). They also tested the effectiveness of the prodrug head-to-head with methotrexate, and showed that it works well in a mouse model. The prodrug was more effective than the equivalent dose of methotrexate. Should this be replicated in patients, it would mean fewer side-effects, which would mean increased quality-of-life, and improved outcomes since the dose could be increased.
These are exciting results, and plan to further optimise the best compounds, to improve the normal tissue stability further, and to try to improve the amount of drug that is released in the tumour.
If Dr Falconer’s research is successful the project could proceed to clinical trial phases. Ultimately, we could potentially see a new Methotrexate drug into mainstream healthcare which is a more effective and efficient attack against osteosarcoma tumours with dramatically reduced side effects. This will revolutionise patient care and would dramatically change views towards Methotrexate application. - Zoe Davison, Head of Research & Information
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