Scientists Unlock Hidden Potential Of Cutting-Edge Cancer Drugs

Main Category: Cancer / Oncology
Article Date: 21 Mar 2013 - 2:00 PDT


A class of cutting-edge cancer drugs could keep patients alive for much longer than they do now following a major new discovery about exactly how they attack tumours.

Scientists have hailed the finding "unexpected and exciting".

The drugs, known as kinase inhibitors, are some of the most heralded of the new kind of targeted therapies, with 25 already in use and around 400 under development. They treat 5,000-10,000 patients in the UK each year, with that number set to grow as more are approved for use.

Kinase inhibitors work across types of breast, skin, lung and kidney cancer, but while effective often only extend life by around three to six months.

But scientists at the University of Sussex and The Institute of Cancer Research, London, believe they can unlock the true potential of the drugs by changing the way they are used - after uncovering a hidden mechanism of action.

The study was funded by Cancer Research UK and the Wellcome Trust, and is published today (Sunday) in the prestigious journal Nature Chemical Biology.

Excitingly, the mechanism identified applied in precisely the same way to each of four kinase inhibitors tested, all of which are already in use as cancer treatments:

• Vemurafenib, which treats cancers caused by a mutation of a gene called BRAF, including many melanoma skin cancer patients
• Lapatinib, which treats patients with aggressive, HER2-positive breast cancer
• Sorafenib, which treats many patients with kidney cancer
• Erlotinib, which treats many patients with non-small cell lung cancer.

Researchers found that the conventional assumption of how kinase inhibitors work against cancers told only part of the story.

The drugs had been thought to work solely by blocking the cell signalling function of enzymes called kinases - which play an active role in many cancers - by preventing them from binding to ATP, the basic unit of energy in cells.

But the new research found that at high doses, the drugs also prevented kinases from linking up with a complex of molecules in cells called the Hsp90-Cdc37 chaperone system, which is essential for maintaining the stability of proteins. The team showed that this 'chaperone deprivation' actually caused the destruction of the cancer-causing kinases and halted the growth and division of cancer cells.

The researchers now plan to conduct clinical trials using kinase inhibitors at higher doses but with rest periods to take advantage of the new mechanism - and believe the new method has the potential to keep cancers at bay for much longer.

Study co-author Professor Paul Workman FMedSci, Deputy Chief Executive of The Institute of Cancer Research (ICR), said: "We already knew these drugs were very effective, but we now think they could be even better. We found that several clinically used kinase inhibitors could not only disable cancer-causing kinases but also cause their destruction. It's an unexpected and exciting discovery, with major implications for how to dose these drugs to help patients live for longer.

"We hope to launch a clinical trial in the next year to test the benefits of delivering kinase inhibitors in a way that should maximise their impact in destroying their targets. There is more work to do to prove the benefit to patients, but these drugs are already approved so there are fewer regulatory burdens than usual to overcome to test our new idea."

Study co-author Professor Laurence Pearl FRS, Professor of Structural Biology in the Medical Research Council Genome Damage and Stability Centre at the University of Sussex, where he also heads the School of Life Sciences, said: "This discovery could really improve the impact of these targeted treatments, which are already becoming important agents in modern cancer therapy. Our work has revealed their hidden power to promote the destruction of the kinases that drive cancer, which hasn't so far been exploited in their clinical use.

"It shows how important it is to understand the basic biology of how cancer drugs work. We have more work to do to understand this mechanism fully, but we are optimistic that our discovery will help many patients live for longer."

Dr Julie Sharp, Senior Science Information Manager at Cancer Research UK, said: "Cancer Research UK scientists have helped to develop and test a number of kinase inhibitors. Having a better understanding of how these drugs work means that researchers can now try and fine tune their use to make them even more effective and improve survival for cancer patients."

Dr Michael Dunn, Head of Molecular and Physiological Sciences at the Wellcome Trust, said: "This discovery emphasises the fundamental importance of using biology to help us understand how cancer drugs work. This is a very surprising and interesting result which could lead to much better therapies in the future." Professor Laurence Pearl FRS

Professor Laurence Pearl FRS is Professor of Structural Biology in the Medical Research Council Genome Damage and Stability Centre and heads the School of Life Sciences at the University of Sussex. For the previous 10 years Professor Pearl was Professor of Protein Crystallography at the ICR.

Professor Pearl's seminal contributions to scientists' understanding of the recognition and repair of DNA damage and the function of molecular chaperones such as HSP90, was recognised in 2008 with his election as a Fellow of the Royal Society (FRS).

Professor Paul Workman FmedSci

Professor Paul Workman FMedSci is one of the world's leading cancer drug discoverers. He is deputy chief executive of the ICR.  He is also director of the Cancer Research UK Cancer Therapeutics Unit at the ICR - the world's largest multidisciplinary academic cancer drug discovery and development initiative.

Under Professor Workman's directorship, the Cancer Therapeutics Unit has helped discover and develop many important new cancer treatments, including the prostate cancer drug abiraterone, which was approved for use by the NHS in 2012. Professor Workman also led the ICR teams that in partnership discovered the leading inhibitors of HSP90 (AUY922) and PI3 kinase (GDC-0941) which are now undergoing clinical trial. In recognition of their success in drug discovery and development, Professor Workman's team and colleagues at The Royal Marsden NHS Foundation Trust received the prestigious American Association of Cancer Research Team Science Award in 2012.

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