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Finding the right combination

The dream of a single pill to cure cancer, a magic bullet that stops the disease in its tracks, is one that now looks a little outdated.

Organisations like The Institute of Cancer Research, London, have been instrumental in showing that cancer is made up of many different molecular sub-types, each of which responds differently to treatment.

And as our understanding of the genetic complexity of cancer has grown, so researchers have increasingly come to believe that combinations of targeted therapies, specifically hitting a number of pre-defined molecular targets at once, represent the best hope of defeating the disease.

Many selective molecularly targeted drugs are initially successful, only for tumours to develop resistance against them – but combinations of targeted therapies stand a better chance of delivering sustained effectiveness.

That’s the view of a group of leading researchers from the ICR and The Royal Marsden NHS Foundation Trust, who set out their vision for the future of combination therapy in a landmark review in the Journal of Clinical Oncology.

Dr Timothy Yap, Dr Aurelius Omlin and Professor Johann de Bono set out their views and propose new strategies to accelerate and enhance translational research into novel drug combinations and their development in the clinic.

The approaches they set out represent a big change in thinking on cancer treatment. Most new drugs, until now, have simply been expected to be better than those already available as individual drugs. Now, it might be that a drug’s value is only shown in combination with other novel therapies.

Dr Timothy Yap, National Institute for Health Research Academic Clinical Lecturer at the ICR and The Royal Marsden, said: “There are now many targeted therapies which are effective at treating different types of cancer, but we can do even better. For example, patients often develop resistance to treatments, meaning that they stop effectively fighting their tumour.

“Many of these drugs can also be disappointing when used individually, and only really reveal their true potential when used in combination with other therapies. Therefore we need to identify and overcome such issues, in order to deliver the maximum likelihood of patient benefit. This should also accelerate drug availability to the patients that need them, so that personalised medicine can become a reality.”

In the paper, the authors propose a number of novel strategies to ensure that drug combinations are optimally developed. They stress the importance of robust preclinical models to test a drug combination’s effectiveness before it reaches the patient. And they focus on the development and incorporation of effective predictive biomarkers, so that the right patients can be chosen on which to test a drug combination in clinical trials.

In addition, because of the increased complexities of treating patients with a drug combination, they advocate the testing of different doses at different frequencies of drugs in clinical trials. This would be guided by how toxic the drug is, and the effect it has on the body and vice versa.

The authors also acknowledge and discuss challenges in assessing the effectiveness of a drug combination, particularly when evaluating an individual drug which has already shown patient benefit. They suggest that a patient who experiences resistance to an individual treatment on a clinical trial should be moved seamlessly to a suitable combination. If the combination then works this would add to the weight of evidence in support of two drugs being better than one.

Professor Johann de Bono, Professor of Experimental Cancer Research at the ICR and honorary consultant at The Royal Marsden, where he is an honorary consultant in medical oncology, said: “We have made a lot of progress in discovering new targeted treatments over the past few years. Now, the challenge is to ensure the right combination of drugs actually reach the right patients who can most benefit from them. That won’t always be easy, which is why we need academia, the pharmaceutical industry and regulatory bodies to work together to ensure we develop effective combination strategies to help save and extend lives of those diagnosed with cancer.”

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