Developing better treatments for breast cancer
When Rob Sutherland, who was recently awarded the 2010 NSW Premier’s Award for Outstanding Cancer Researcher, first started out in cancer research, he was motivated by the heavy burden of breast cancer on women and the radical surgical approaches of the day to do something about it.
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“There had to be a better way of managing the disease!” he says.
One answer was tamoxifen: an antagonist of the oestrogen receptor in breast tissue used in the treatment of breast cancer.
“Tamoxifen was the first anti-cancer agent that targeted a biological mechanism, i.e. oestrogen-induced cell proliferation, and provided a paradigm for less aggressive approaches to the management of cancer,” Rob says. “With the subsequent success of tamoxifen, and more recently other therapies that target oestrogen action, i.e. aromatase inhibitors, our focus has been on better understanding the molecular basis of disease and there are now many examples of this more targeted approach to therapy leading to successful new treatments with reduced side effects.”
Together with his long-standing colleague, Professor Liz Musgrove, a Cancer Institute NSW Fellow at the Garvan Institute of Medical Research, Professor Sutherland’s team has continued to make major advances in this area.
“Our studies illustrate how a deeper understanding of how oestrogen affects gene expression and normal cellular physiology,” he says. “Also, how these mechanisms are subverted in endocrine resistant disease, and can aid in the development of new biomarkers and therapeutic targets for the better management of breast cancer.”
Liz Musgrove is currently leading the research and is heading towards new breakthroughs about understanding the role oestrogen plays in breast cancer. “We wanted to know how, at a molecular level, the female hormone oestrogen regulates cell division, growth and survival,” she says. “Because oestrogen not only drives cell proliferation in the normal breast, but also promotes the development and progression of breast cancer, another question is whether deregulation of the processes that oestrogen controls may make drugs that interfere with oestrogen action, for example the antiestrogen tamoxifen, less effective in the clinic.
“We have approached these questions by undertaking a genome-scale investigation of the genes that are regulated by oestrogen as it promotes cell division, and then classifying these oestrogen-regulated genes on the basis of the cellular process they are involved in,” says Liz. “By drawing on databases of information from other experimental models we identified networks of functionally-connected genes that will help us to select those most likely to play a major role in cell division, growth and survival, and further study their precise role in the cell.”
In collaboration with colleagues at the Peter MacCallum Cancer Centre in Melbourne, Professor Musgrove’s team also showed that the expression of these networks of genes could be used to divide women treated with tamoxifen into those with better or worse outcome.
“Importantly, this analysis suggested that two of the networks independently predicted outcome, meaning that they identified subsets of women who responded poorly, but did so for different reasons,” she explains. “We are now extending this work by using newly developed technology for experimentally screening large numbers of genes to find those oestrogen-regulated genes that are likely to be central drivers of cell cycle progression and cell survival.”
As many as three-quarters of women with breast cancer are potentially treatable with drugs such as tamoxifen and aromatase inhibitors. However, even though these drugs are effective and well-tolerated, not all women respond. Unfortunately, many women who do respond initially will also eventually relapse with a recurrence of their breast cancer. This is a fact that drives the research into early detection and prognosis.
“Identifying women who may benefit from early treatment with additional chemotherapy is a pressing clinical need,” says Liz. “An equally large challenge is to identify new therapeutic targets and develop novel therapies for treating breast cancer that is resistant to the currently-available therapies, which we are beginning to address using functional genetic screens.”
Now our vision of being able to conduct multidisciplinary cancer research at the highest international standards and have it translated into real benefit for cancer patients may be a reality rather than fiction.
- Professor Rob Sutherland
Professor Musgrove’s team are now working on loss-of-function genetic screens in collaboration with Dr Kaylene Simpson at the Victorian Centre for Functional Genomics (VCFG) based at the Peter MacCallum Cancer Centre in Melbourne and gain-of-function screens in collaboration with Professor Tom Gonda and his team at the ARVEC facility based at the Diamantina Institute, University of Queensland, in Brisbane.
The breakthroughs in understanding the genes of breast cancer have also enabled Professor Sutherland’s team at the Garvan Institute to translate their research into findings for other cancers. “In recent years the experience in the breast cancer area facilitated new programs in prostate, pancreatic, ovarian and other cancers where we have employed contemporary gene discovery tools in genomics, including next generation sequencing through the involvement of Professor Andrew Biankin, another Cancer Institute NSW Fellow, in the ICGC pancreatic cancer project, and gene expression analysis to identify new biomarkers of diagnosis, disease progression, disease outcome and therapeutic responsiveness,” he says.
With these exciting discoveries that have been recognised on the world stage, Professor Sutherland is optimistic about the future of cancer research in NSW.
“Until the advent of the Cancer Institute NSW, NSW had been the ‘poor relative’ in cancer research in Australia with many impediments, not the least of which were funding and infrastructure, to conducting world-class cancer research,” says Professor Sutherland. “But, now our vision of being able to conduct multidisciplinary cancer research at the highest international standards and have it translated into real benefit for cancer patients may be a reality rather than fiction.” The recent funding of The Kinghorn Cancer Centre, a joint Garvan Institute and St Vincent’s Hospital venture with a focus on translational research, integration of research and cancer treatment, and personalised medicine, will further facilitate these goals.
Professor Musgrove agrees, but stresses that for this to happen, researchers shouldn’t be afraid to think outside the square. “To capitalise on this opportunity we need to embrace diversity in experimental models and approaches, in the aspects of cancer research that we study and in the career paths of the people we support,” she says.