The discovery of a brand new class of cancer drugs that knock out the defences tumours use to become resistant to treatment has been recognised by the award of one of the UK’s most prestigious cancer research prizes.

The award was presented at the National Cancer Research Institute (NCRI) Cancer Conference, the UK’s leading annual conference of cancer researchers.

HSP90 inhibitors have sparked excitement in the cancer research world for their ability to attack tumours that have stopped responding to existing drugs – and could be used against a wide range of cancers including lung, breast, prostate, ovarian and colon.

Drug resistance is widely recognised as the major challenge in cancer treatment, even with the new targeted therapies, and HSP90 inhibitors have already entered clinical trials worldwide.

Now scientists from The Institute of Cancer Research, London, and The University of Sussex have won the 2013 Cancer Research UK Translational Cancer Research Prize for their pioneering work to understand how HSP90 works, then discover the new drug class and take the first members of it into the clinic.

The award is given annually for outstanding research that bridges the gap between science in the laboratory and the development of new treatments for patients.

The prize marks the culmination of more than 10 years of work to elucidate the structure and function of a super-protein called Heat Shock Protein 90 (HSP90), which oversees a range of processes that are essential for cancer cells – and to design and evaluate drugs that target HSP90, including one called AUY922 which is now showing promise in patients with drug-resistant cancers. HSP90 inhibitors have shown encouraging results in both breast and lung cancers and the more advanced HSP90 inhibitors are now progressing to phase III trials.

Because HSP90 is critical for many processes that are fundamentally important in cancer, inhibiting it with the new drugs hits cancer hard in several different ways simultaneously, undermining its growth, survival and spread. Targeting HSP90 also knocks out several important molecular mechanisms that are used by cancers as a way of side-stepping the effects of treatment.

The most promising, advanced trials so far include phase II clinical studies in patients with HER2-positive breast cancers which have become resistant to the commonly used antibody drug trastuzumab, and also in patients with non-small cell lung cancer who have become resistant to the widely used drugs erlotinib and crizotinib, which target two tumour pathways driven by cancer genes called ALK and EGFR. HSP90 inhibitors work by causing the destruction of the protein products of these genes, and patients can be selected for treatment using markers for them.

Both the clinical results and the new prize are a vindication for the collaborative team, who met with years of scepticism from many doubters in the scientific community and industry who believed that HSP90 would not work as a target for cancer therapy. Critics argued that the approach was too risky and that HSP90 inhibitors would have unacceptable side-effects.

The research team reasoned that it was possible to develop effective and well-tolerated drugs because all of their ‘hits’ would be specific to cancer. They were convinced that because cancer cells are more dependent on HSP90 than healthy cells there would be a window of opportunity to achieve anti-cancer responses while minimising side-effects – and their prediction has now been shown to be correct.

Professor Paul Workman, Deputy Chief Executive of The Institute of Cancer Research and Director of the Cancer Research UK Cancer Therapeutics Unit, initiated and led the HSP90 drug research programme, and is one of the recipients of the new award.

He said: “This is a fantastic achievement for our team and terrific recognition for our translation of basic knowledge of HSP90 into drugs like AUY922 that are now showing activity in cancer patients. In the shorter term, HSP90 inhibitors are likely to be used in patients who have become resistant to current treatments, but in the future they could play an even bigger part in tackling cancer as an early-stage treatment and preventing drug resistance arising.

“Our multidisciplinary team has played a leading role in moving HSP90 from a poorly appreciated target to one of the most actively pursued in the drug industry today, in spite of the initial incredulity and scepticism from many who questioned whether we could discover an effective and safe drug acting on HSP90.”

Co-recipient Professor Laurence Pearl, Professor of Structural Biology at the University of Sussex, led the team’s research into the fundamental understanding of how HSP90 functions before moving from the ICR in 2009.

He said: “This award is recognition for a truly multidisciplinary scientific approach, which brought together basic, translational and clinical research in a pioneering collaboration. It was structural biology that gave us the insights into the 3D structure and function of HSP90, which in turn helped us to design prototype drugs which could disrupt its action.

“I’m proud that we have been able to carry out this successful research in the UK academic sector – arguably, no other group of researchers in the world could have done this work.”

Dr David Scott, Director of Science Funding at Cancer Research UK, said:

“I’d like to congratulate this pioneering research team for winning the 2013 Cancer Research UK Translational Cancer Research Prize, which is one of the most prestigious awards of its type. The HSP90 team is an exceptional group that exemplifies the broad skill set needed to build and test therapeutic small molecule inhibitors. Their research is a model for academic drug development that should inspire others.”

Source: ICR