One-two combination floors cancer | University of Oxford
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One-two combination floors cancer

Jonathan Wood

A new tag-team approach to combating a type of skin cancer is showing early promise in the lab. The scientists in Oxford and Spain investigated a two-drug combination to better target cancer cells in melanoma.

The approach uses one drug to drive melanoma cancer cells that are invasive to become sensitive to a second drug. This second drug is a new compound that is activated very specifically in melanoma cells and not other cells in the body.

'Importantly, because the new drug is only activated in melanoma cells, there should be no side effects,' says Professor Colin Goding from the Ludwig Institute for Cancer Research at the University of Oxford.

The first drug, methotrexate, is an existing one that is currently used for diseases such as arthritis and psoriasis. The researchers found that methotrexate stops melanoma cells spreading to other parts or the body, and also sensitises the cells to the second drug, a new compound called TMECG, which kills the cancer cells.

When given alone, neither drug has any effect. But together, the researchers show that the two drugs kill melanoma cells very effectively in the laboratory and also in animal models – including cancer cells that are resistant to current therapies.

The research team – jointly led by Professor Goding and Professor José Neptuno Rodriguez-López from the University of Murcia in Spain – have shown the potential of the technique in human cells in the lab and in mice. They have published their findings in the journal Cancer Cell.

'The work is still at an early stage,' cautions Professor Goding. 'Although this combination treatment works very effectively in animals, we still need to improve the stability of the new drug in the blood to make it effective in patients. We also need to check that there is no toxicity associated with the new drug, though our preliminary results look very good.'

The researchers believe that it will be combinations of treatment approaches like this one that will help floor cancer, and deal with the great problem of tumours acquiring resistance to cancer therapies.

'The major problem with cancers is their capacity to become resistant to therapy and to spread to many parts of the body,' explains Professor Goding. 'Resistance is caused by there being different kinds of cancers cells within tumours, some of which may be resistant to therapy.'

Melanoma is a rare and serious type of cancer that begins in the skin and can spread to other organs in the body. The most common sign of melanoma is the appearance of a new mole or a change in an existing mole. Melanoma caught early can be treated very effectively by surgery. But unfortunately there is no long-term effective therapy once the disease has spread.

'There is a new drug called vemurafenib that gives a good response for the 50% of patients whose cancers have a mutation in the BRAF gene, but resistance occurs within some months,' says Professor Goding. 'Chemotherapy is largely ineffective, and though there is some success with a new form of immunotherapy, this is still at a very early stage.'

He outlines how cancers like melanoma may need to be treated in future: 'We envisage that treating cancer must be done using combinations of therapies that work by completely different mechanisms, such that cells resistant to one therapy would be sensitive to the other.

'We may need to give these combinations sequentially or in combination. So, if therapy A kills the vast majority of cancer cells there will be only few left that are resistant to therapy A, but should still be sensitive to therapy B. Since after therapy A there are few cells that survive, there is much less chance of resistance to therapy B occurring.

'In other words to treat cancer successfully we may need to think about the way we treat a bacterial infection, with combinations of antibiotics. Combinations of anti-cancer therapies may have much more success than giving one treatment alone.'

The researchers hope that the new strategy they have identified will form one treatment approach that, in combination with others, may contribute to a successful anti-melanoma therapy that is effective in the long-term.