The research, reported in the journal Oncogene, provides new insights into the regulation of a family of proteins called Fibroblast Growth Factor Receptors (FGFRs) which play a key role in controlling cell growth and are frequently implicated in cancer when they become deregulated, for example by mutations. These findings may pave the way for new therapeutic targets and a greater understanding of tumour cells’ versatility to overcome therapies targeting this pathway.
Cartoon and surface-rendered representation of the ATP-binding pocket of human FGFR1 in complex.
Credit: Cook et al/Macmillan Magazines 2012
Dr Simon Cook led the research at the Babraham Institute, which receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC). He said “FGFR proteins are found at the cell surface and transmit signals for cells to survive and grow. We are interested in FGFRs because they are important in normal biological processes such as development and wound repair. However, researchers are increasingly interested in the FGFRs as targets to treat cancer. In certain cancers, including breast, gastric, and bladder cancer, as well as multiple myeloma, FGFR proteins are either mutated or their numbers are much higher than normal and such cancer cells become ‘addicted’ to FGFR proteins, needing them to grow.”
Researchers at the pharmaceutical company AstraZeneca have developed a new drug that blocks these FGFR proteins in the hope that this will also stop cancer growth. Working with AstraZeneca, Dr Cook and his team have now shown that this drug, called AZD4547, can inhibit the growth of gastric, bladder, breast and myeloma cancer cells, but only those tumours that are addicted to FGFR. They have also looked at how such FGFR-addicted tumours adapt to new FGFR inhibitors such as AZD4547.
Dr Cook explained, “We have found that tumours adapt by switching to a new mutant form of FGFR that can no longer bind to or be inhibited by the drug. This is important because even the most successful anti-cancer drugs are limited by the extent to which tumour cells adapt and develop resistance. If researchers can identify how tumours adapt to these new drugs it may allow doctors in the clinic to develop strategies to prevent such resistance in the future.”
A significant problem in treating tumours is their ability to develop resistance to new chemotherapeutic drugs, which causes disease relapse. Arising from this work, Dr Cook has recently been awarded two new research grants to continue his work on acquired drug resistance in tumour cells. One of these grants is funded by the Association for International Cancer Research (AICR) and will continue work on AZD4547. The other is funded by Cancer Research UK (CRUK) and will study how tumour cells adapt to drugs that inhibit a key tumour growth pathway inside cells called the ERK pathway. Both grants will continue the collaboration with AstraZeneca, representing a tripartite approach to cancer research involving basic scientists, like Dr Cook, cancer charities, like AICR and CRUK, and the pharmaceutical sector.
The Babraham Institute is a world-leading centre for studying the basic biology of signalling inside and between cells, supporting BBSRC’s mission to drive advances in fundamental bioscience for better health and improved quality of life. It also seeks to translate its work through collaborations with industry and charities to maximise social and economic impact.
Institute Director, Professor Michael Wakelam commented, “This is an excellent example of how Babraham Research continues to attract significant financial support from both industry and charities, to investigate the basic biology behind tumour cells’ ability to overcome therapies, which is an important concern for industry and for patients’ quality of life. Ineffective therapies also pose a significant health economic cost. ‘Knowledge Exchange’ partnerships between academia, industry and charities are critical for ensuring basic research delivers the widest benefit to society and the economy.”
This research was funded by the BBSRC, AstraZeneca, and a BBSRC CASE-studentship with AstraZeneca awarded to the lead author, PhD student Vikki Chell.
Dr Cook added, “CASE studentships provide excellent training for PhD students, giving them a cutting edge research project and first-hand experience of working in the commercial sector on applied/translational projects. In addition, in today’s tough funding climate, it provides an important way to pump-prime collaborations between academics and the pharmaceutical sector.”
About The Babraham Institute
The Babraham Institute, which receives strategic funding (£22.4M in 2010-11) from BBSRC, undertakes international quality life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. The Institute’s research provides greater understanding of the biological events that underlie the normal functions of cells and the implication of failure or abnormalities in these processes. Research focuses on signalling and genome regulation, particularly the interplay between the two and how epigenetic signals can influence important physiological adaptations during the lifespan of an organism. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and healthier ageing. www.babraham.ac.uk
AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialisation of prescription medicines for gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease. www.astrazeneca.com
BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.
Funded by Government, and with an annual budget of around £445M (2011-2012), we support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.
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