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Targeting Hsp90

We determined the structure and function of Heat Shock Protein 90 (Hsp90), a molecular chaperone which is critical for the growth and survival of cancer cells.

Bioassay (Jan Chlebik for the ICR 2011)

Photo: Jan Chlebik for the ICR

We worked with partners to discover the cancer drug AUY922, which has shown clinical activity in drug-resistant breast and lung cancers. The drug is the culmination of two decades of multi-disciplinary research at The Institute of Cancer Research, London into the drug's target, Heat Shock Protein 90 (Hsp90), which has spanned the research pathway from bench to bedside.

A growing interest

Hsp90 caught the eye of ICR scientists in the 1990s. At the time there was little support for Hsp90 as a drug target, but there were reasons to be interested. Hsp90 is a ‘molecular chaperone’ which cells rely on during the assembly of proteins, and which helps to protect proteins and cells from a range of stresses like heat.

This protective effect is especially important for the abnormal proteins driving cancer, which would be unstable without its support.

A major advantage of targeting Hsp90 is that its inhibition can lead to the degradation of multiple different cancer-causing proteins by the cell’s garbage-disposal system. This gives Hsp90 inhibitors the ability to overcome drug resistance and potential to be used as a single agent or in combination with other targeted agents.

Kick-starting research

In 1997, Professor Laurence Pearl and Dr Chris Prodromou published the crystal structure of Hsp90, kick-starting research into how the protein interacts with its partners and the proteins it supports.

Professor Paul Workman, who at the time was Director of the Cancer Research UK Cancer Therapeutics Unit at the ICR and is now our Chief Executive, recognised the potential of Hsp90 as an innovative drug target and worked with Professor Pearl to launch a programme of drug discovery, screening for drug candidates which might block the active site identified on Hsp90.

The team identified a promising lead in family of small molecules, the pyrazole resorcinol series, and helped to demonstrate the practicality of targeting Hsp90 as a strategy for defeating cancer.

With interest in Hsp90 growing, the team collaborated with the biotech company Vernalis to refine and optimise their Hsp90 inhibitor leads using structure-based design, with AUY922 emerging as a frontrunner clinical candidate.

From bench to licence

The drug was licensed in 2004 to Novartis which has taken it through early-phase clinical development, demonstrating its safety and clinical activity in drug-resistant breast and lung cancer.

The ICR has remained a central partner in the drug's development, with Dr Udai Banerji leading the phase I trial at the Drug Development Unit at the ICR and The Royal Marsden NHS Foundation Trust.

Having paved the way with discovery research into Hsp90’s structure and biology, then designing and optimising the drug AUY922, the ICR is now learning from the results of blocking Hsp90 in the clinic, including making surprising new discoveries about precisely how Hsp90 inhibitors work in cells – with implications for how best to use them in patients.

It makes this one of the finest examples of the ICR's team science taking research from bench to bedside and back again.

Award-winning research

With Hsp90 now one of the hottest targets in the drug industry — more than 20 other Hsp90 inhibitors are now in clinical trials around the world — it's no wonder the ICR's Hsp90 programme has picked up several prestigious awards.

In 2013, the teams led by Professors Workman and Pearl won the prestigious Cancer Research UK Translational Cancer Research Award for this collaborative, multi-disciplinary research on the basic understanding of Hsp90 and the discovery of drugs that inhibit it.

And in 2010, Professor Workman was the winner of The Royal Society of Chemistry’s George and Christine Sosnovsky Award in Cancer Therapy for ‘his seminal research on the role of chaperone proteins in cellular processes and the application of this knowledge at the forefront of anti-cancer drug discovery’.