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 is this project aiming to achieve?

Dr Robert Falconer and his team at the University of Bradford are aiming to create a chemically modified methotrexate ('prodrug'). This prodrug treatment aims to combat 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.

The way Dr Falconer and his team have achieved this is by differentiating what properties are present in osteosarcoma tumour cells that are not present in normal body tissue cells.

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.

The Plan

Before the team can test this approach in patients with osteosarcoma, lab research needs to be conducted by the team to develop and refine the new prodrug treatment. The following phases will be undertaken:

  1. The team will make a series of potential prodrugs. These modified Methotrexates will have a chain of amino acids attached to them (amino acids are the building blocks to making proteins). For this research, the amino acid chain will be used in helping the prodrug stay inactive throughout the normal tissues until the amino acid chain releases the Methotrexate into the tumour microenvironment. The prodrugs which appear to be the best candidates will be taken forward to phase two.
  2. Testing will be conducted on different types of tissues in vivo including the liver, lungs, kidney, heart and plasma. It will involve testing the chemical stability of the prodrug. Therefore, the prodrug which is best at staying inactive in these normal body cell tissues, but is best released from the amino acid chain into the tumour will move on to phase three.
  3. The prodrug which is advanced to the final stage will be applied to a human osteosarcoma patient. At this stage, the team will be evaluating the prodrugs efficacy in killing osteosarcoma tumour cells compared to an equivalent dose of ordinary methotrexate. The team will also monitor and record any side effects of this new approach.
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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