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Breaking through the barriers to targeted therapy

Posted on 26 September, 2013 by Joe Dunckley
A drive to take our discoveries from the bench to the bedside lies behind much of the research that we do here at The Institute of Cancer Research, London. Translational research — from fundamental findings of facts about human biology, to advances in cancer care and therapy — has become an especially large part of what we do in recent years, thanks to the great many new insights into the molecular basis of cancer that have been (and are being) turned up by genomics. This genetics revolution at the laboratory bench is being translated into a personalised medicine revolution in the clinic, with the development of new targeted therapies that attack the specific molecular drivers of cancer cells.

But this bench-to-bedside journey for targeted therapies is no simple stroll in the park. Three team leaders from The Institute of Cancer Research (ICR) last week joined other global leaders in cancer research at the Wellcome Trust's genome campus in Cambridgeshire for the Pharmacogenomics and Targeted Therapies Conference, where they discussed current challenges in the design, development and implementation of new therapies.

Computational Biology & Chemogenomics team leader, Dr Bissan Al-Lazikani, spoke about the challenges of working with the astronomical volume of data from genome projects — or, rather, greater than astronomical, with every one individual genome sequenced producing more data than 20 years of the Hubble Space Telescope. We have gathered vast libraries of data already, and there are important insights waiting to be found in our databases. Bissan's team ensure that those insights do not languish in the dark. The team devise new computational methods and tools for processing, sharing and interpreting that data, so that we can keep up with the creation of new piles of data and ensure that we make the most of it.

Meanwhile, Professor Johann de Bono, Professor of Experimental Cancer Medicine and head of the ICR and The Royal Marsden's joint Drug Development Unit, spoke about the lessons that can be learned from the development of the first targeted therapies, and how drug development can be faster and more precise — cutting the risk that new therapies will fall by the wayside on their journey to the clinic.

Finally, our Deputy Chief Executive and Director of the Cancer Research UK Cancer Therapeutics Unit (CTU), Professor Paul Workman, spoke about one of the greatest of all challenges facing targeted therapies: drug resistance. We wrote about this a couple of weeks ago. Because of the way that cancer cells pick up mutations, tumours become diverse populations of different cells driven by a variety of mutations. So when we believe that we have identified a therapy that can target the mutation driving a patient's cancer, it might turn out to be effective against only some of the cells in the tumour — enabling others to evade the drug. Paul spoke about some of the discrete challenges that are being tackled in order to extend the success of targeted therapies to more cancers. Future strategies look set to rely on combinations of treatments, which together target several of mutations that can drive cancer cells — so that no cells can evade all of them. But to enable such combination targeted therapies, we will need to continue discovering and developing new drugs for as yet untackled molecular targets — including some cancer-driving mutations which have previously been dismissed as undruggable.

Paul also spoke about the potential for using one particular new class of drug his team discovered in the CTU at the ICR, the HSP90 inhibitor AUY922, to overcome or even prevent drug resistance. The resistance-busting properties of HSP90 inhibitors result from their ability to destroy multiple cancer-causing proteins simultaneously, hence limiting the options for tumour escape mechanisms that lead to drug resistance. Paul presented new data explaining how HSP90 inhibitors cause the breakdown of cancer-causing proteins. In addition he described new genome-based screening approaches to find new drug targets in pathways related to HSP90.

The genetics-based personalised medicine revolution promises much, and so we periodically hear grumbles when the journey from bench to bedside is perceived to be moving too slowly, or when a stumbling block is encountered. But the ideas discussed at the conference suggest that cancer's translational researchers are aware of the challenges they face, and are full of ideas for how to confront them.
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