‘Molecular relay race’ at the heart of new targeted cancer therapy

A big problem in cancer treatment is how to deliver enough of the drugs needed to treat the tumour without causing excessive side effects. To make matters worse, cancers can develop resistance to drugs over time, meaning that increasingly higher doses and more potent cocktails of drugs are often needed to tackle the disease.

But more powerful drugs usually mean more serious side effects. So there comes a point when increasing the dosage of the drug any further simply isn’t possible due to the damage that powerful cancer drugs can do to the body in large amounts.

So Dr Mark Middleton and his team, based at Cancer Research UK’s Experimental Cancer Medicine Centre (ECMC) in Oxford, have discovered a possible way around this challenging problem through the development of a new, more targeted cancer therapy.  Their results are published this week in the journal Science Translational Medicine.

Targeting cancer

Rather like a molecular relay race, the new treatment relies on a chain of events that culminates with the activation of a potent drug specifically in cancer cells.

The first ‘runner’ in the relay is a chemical called EPO152R, which travels through the blood and into cancer cells, where it activates the second ‘runner’ – a protein called NQO2.  This is an enzyme found in high levels in certain types of cancer cell, including bowel and liver tumours.

This ‘activated’ NQO2 enzyme can now activate the third and final ‘runner’ – a harmless ‘pro-drug’ chemical, catchily named CB1954. It does this by converting it into a potent cancer-killing drug.

Because healthy cells have lower levels of NQO2 than healthy cells, they’re unable to produce a large amount of the final active drug, so – at least in theory – they’ll avoid serious damage – and there’s less chance of side effects. Targeting the drug specifically to the tumour in this way allows a much higher dose to be given, maximising its ability to kill cancer cells without harming normal ones.

Early promise

In their new paper, Dr Middleton and his team published results from a clinical trial of the experimental new treatment. Thirty-two patients with advanced cancer were given a combination of EPO152R and CB1954.

As with all early-stage clinical trials, this study was primarily finding out what dose of the drug would be safe, rather than measuring its effectiveness in people with cancer.

The trial showed that the ‘molecular relay race’ concept works – they found that the drug was activated in the patients’ tumours. And it also allowed the researchers to work out the highest dose they could safely use before the treatment caused severe side effects. However, the treatment still caused a number of side effects, including tiredness, diarrhea and vomiting.  But the early results are encouraging, and suggest that the therapy warrants further trials.

This trial was a collaboration between three of the 19 ECMC centres situated across the UK – based at Oxford, The Institute of Cancer Research and UCL.  The ECMCs are an exciting Cancer Research UK initiative set up to provide patients with new opportunities to participate in clinical trials for the latest and most innovative cancer treatments.  It’s fantastic to see exciting new approaches coming through from the lab to the clinic, and this early-stage new treatment is just one of the many potential life-saving therapies we hope to bring to patients in the future.

Ailsa Taylor, Cancer Research UK press officer

Reference:

Middleton, M. et al, (2010). Quinone Oxidoreductase-2-Mediated Prodrug Cancer Therapy Science Translational Medicine, 2 (40), 40-40 DOI: 10.1126/scitranslmed.3000615