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 will be presented on Monday 4 November 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 (Herceptin), 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, 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.”
Notes to Editors
*One of the most advanced HSP90 inhibitors, called AUY922 (1), arose directly from the prototype drugs discovered by the research team at the ICR and has shown promising responses in phase II clinical trials in patients with drug-resistant forms of breast and lung cancer.
The project that led to the discovery of AUY922 was initiated in 2001 by Professor Paul Workman’s team at The Institute of Cancer Research, London, who discovered the first prototype drugs of this new generation of HSP90 inhibitors. The ICR researchers then collaborated with Vernalis plc (LSE: VER) to identify AUY922 as a drug candidate. This was then on- licensed by Vernalis plc to the global pharmaceutical company Novartis who are now responsible for clinical testing of AUY922 in cancer patients.
Recently published data from an earlier, phase I trial led by researchers at the ICR and The Royal Marsden NHS Foundation Trust found that AUY922 had a good safety profile and showed evidence of inhibiting the HSP90 target and blocking its cancer-promoting effects in patients with advanced drug-resistant cancers (2). These beneficial effects were as predicted by the prize-winning team.
HSP90 is a master protector in healthy cells, saving them from environmental stress. But in tumours, cancer cells turn the HSP90 protein to their own ends by using it to subvert the natural process of controlled cell death. HSP90 also stabilises many mutated proteins involved in some cancers – including their drug-resistant forms – allowing them to wreak havoc with cellular replication machinery and cause uncontrollable cell division and spread of cancer cells.
The ICR programme is a leading example of potential large-scale patient benefit emerging from risk-taking drug discovery research in the UK academic sector, bridging the so-called ‘innovation gap’ between the non-profit sector and industry. New clinical trials led by pharmaceutical companies have only been made possible thanks to an integrated, broad range of earlier research on HSP90 from ICR and now Sussex scientists, funded by UK research charities such as Cancer Research UK and the Wellcome Trust, and first-in-human clinical trials at the ICR’s partner institution, the Royal Marsden.
The £25,000 prize will be used by Professors Workman and Pearl to help continue their ongoing collaboration, the ongoing productivity of which is shown by their recently published (3) new insights into the mechanism of antitumour action of clinically approved targeted cancer drugs known as kinase inhibitors – the same drugs to which resistance develops in patients that can be now overcome with HSP90 inhibitors. The unexpected new mechanism involves the protective role of HSP90 as a ‘molecular chaperone’ for cancer proteins and the novel findings support the clinical use of combinations of HSP0 inhibitors and kinase drugs. Further research by the collaborative ICR and Sussex team is identifying new targets related to HSP90 for future drug discovery programmes.
- Cancer Research, 2008. Apr 15;68(8):2850-2860
- Clinical Cancer Research, 2013. Jul 1;19(13):3671-3680.
- Nature Chemical Biology, 2013. May;9(5):307-12
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