Associate Professor Swarbrick and his team are looking at the genes that control breast cancer metastasis and drug response. To metastasise, breast cancer cells must leave the breast, travel through the circulation and invade a distant organ. Once there, cells must adapt and survive and while most cancer cells will die in a new hostile environment, in many cases some cells eventually grow causing metastatic tumours.
Our breast cancer research
Garvan is home to one of the largest breast cancer research groups in Australia.
Garvan was one of the first medical research institutes in the world to acquire technology that can sequence a whole human genome at high throughput and low cost.
Whole genome sequencing facilities at Garvan means that breast cancer research teams can sequence breast tumours, vastly increasing our understanding of this disease and leading to better and more effective personalised therapies.
Key areas of investigation
The Cancer Cell Plasticity Laboratory
Cancers are made up of many different cell types, including aggressive tumour-initiating cells (TICs) that can cause metastases, disease recurrence and therapeutic resistance. A/Prof. Christine Chaffer’s lab has discovered that non-aggressive cancer cells (known as non-TICs) can change their biological constitution and enter into the highly aggressive TIC state through a process called cancer cell plasticity. She has also discovered that inhibiting cancer cell plasticity can successfully block tumour initiation and progression.
The Tumour Progression Laboratory
Triple negative breast cancer (TNBC) is an aggressive form of breast cancer with a higher risk of relapse. Using cellular genomics, A/Prof Alex Swarbrick’s lab recently uncovered four new subtypes of cells within triple-negative breast cancer, which contain promising new therapeutic targets for this aggressive disease. One of the new cell types, known as stromal cells, produces molecules that suppress immune cells, which may help cancer cells evade the body’s immune system.
Connie Johnson Breast Cancer Laboratory
Around 75% of breast cancer are driven by dysregulated activity of the Estrogen Receptor (ER). ER targeted therapies are a gold standard therapy but acquired resistance remains inevitable and is associated with ~50% of breast cancer-related deaths. Prof Elgene Lim’s lab is trying to identify the biological mechanisms that underlie this resistance and to establish a clinical trial platform to find new treatments.
Genetics of breast cancer metastasis
"To design better therapies for metastatic breast cancer, we first must understand the ways in which breast cancers evolve during metastasis and evade therapy."
Associate Professor Alexander Swarbrick
Patients without metastasis have a very good prognosis, but once breast cancer has spread, the outlook for patients is very poor.
‘To design better therapies for metastatic breast cancer, we first must understand the ways in which breast cancers evolve during metastasis and evade therapy,’ said Associate Professor Swarbrick. ‘The biological basis of metastatic breast cancer is poorly understood and so few drugs are effective against metastatic diseases.
‘To address these challenges, we are using next-generation sequencing to study the evolution of breast cancers as they respond to the challenges of metastasis and treatment resistance with anti-cancer drugs. We are using cutting-edge genetic studies and single-cell genomics to map metastatic cancers from consenting patients and from state-of-the-art patient-derived xenograft mouse models of breast cancer.
‘We aim to discover the genetic programs and mutations that allow cancer cells to survive and thrive under these conditions, and then use this information to develop drugs that eradicate metastatic cells.
‘Garvan’s excellent clinical collaborations, gene sequencing facilities and world-class collection of breast cancer models provides us with a unique opportunity. This, along with our ability to study genes at the level of the single cell, offers remarkable new insights into these disease processes, as well as new therapeutic strategies, particularly for underserved breast cancer patients.’
Sensitising breast cancer to endocrine therapies
The vast majority of breast cancers express steroid hormone receptors, including the estrogen, progesterone and androgen receptors. Therapies that target the estrogen receptor have transformed the care of patients with these cancers. However, a significant minority of such patients develop resistance to these therapies and relapse from their cancer. There is a critical need to identify new treatments and strategies to overcome treatment resistance to endocrine therapy.
"As a clinician-scientist, I invite patients to be research partners with Garvan and access the precinct’s state-of-the-art research infrastructure, through participation in clinical trials of novel therapies, and through the provision of their tissue that is in excess of diagnostic requirements for research projects."
Associate Professor Elgene Lim
Associate Professor Elgene Lim’s research team focuses on hormone receptors, and identifying treatment strategies to sensitise cancer to endocrine therapies and overcome therapy resistance. Together with Dr Liz Caldon’s group, they evaluate novel therapeutic strategies not currently used in breast cancer, and identify biomarkers that predict response to the treatments. This includes finding new ways to target the androgen and progesterone receptors, which unlike the estrogen receptor, are not routinely targeted in current breast cancer care. By harnessing the interaction of these hormone receptors, they aim to sensitise breast cancer to endocrine therapies and overcome resistance to therapies.
In collaboration with Dr Christine Chaffer, Associate Professor Lim is also evaluating how different subpopulations of cancer cells avoid sensitivity to conventional therapies by adopting a ‘plastic’ state, and how to better target these cells.
A key part of this research includes the development of preclinical models that more accurately predict treatment response in patients. Associate Professor Lim said, ‘As a clinician-scientist, I invite patients to be research partners with Garvan and access the precinct’s state-of-the-art research infrastructure, through participation in clinical trials of novel therapies, and through the provision of their tissue that is in excess of diagnostic requirements for research projects.’
Together with Associate Professor Alexander Swarbrick, he has established a large panel of ‘breast cancer avatars’, where cells from a patient’s breast cancer are implanted into immunodeficient mice to allow research into tumour growth, progression and the evaluation of novel therapeutics.
Associate Professor Lim (Head of the Connie Johnson Breast Cancer Research Laboratory, and Senior Medical Oncologist) leads the comprehensive breast cancer service at Garvan’s Kinghorn Cancer Centre. This includes a multidisciplinary team of surgeons, plastic surgeons, medical oncologists, radiation oncologists, geneticists, psychologists, breast cancer nurses and physiotherapists. Ultimately, Associate Professor Lim, together with his colleagues, aim to improve outcomes in breast cancer patients through the translation of research discoveries into patient care.
The ‘off-switch’ for triple negative breast cancer
Patients with so-called triple negative breast cancers – the 15% of breast cancers that do not have either estrogen (ER) or progesterone (PR) receptors, and do not overexpress the HER2 protein – are younger and have a higher risk of relapse than those with other subtypes of breast cancer.
"Personalised medicine aims to develop treatment tailored to each patient. Progress in personalised breast cancer treatment requires the development of new therapies for underserved breast cancer patients and new tests or biomarkers that can identify the most appropriate treatment for each breast cancer patient."
Associate Professor Alexander Swarbrick
As these tumours lack ER, PR and HER2, they cannot be treated with anti-hormonal or anti-HER2 directed drugs and new targeted therapies are urgently needed. Little is known about the drivers of this disease or what drugs might be most effective for patients with triple negative breast cancer.
Head of Garvan’s Tumour Progression Laboratory since 2008, Associate Professor Alexander Swarbrick also coheads the Breast Translational Oncology Program, where he leads a multidisciplinary team of experts in cell and molecular biology, pathology, oncology and computational biology.
‘The diverse nature of breast cancer means that some women are either over-treated with toxic and expensive therapies, or under-treated because no “targeted” therapy exists for their disease,” said Associate Professor Swarbrick. ‘Personalised medicine aims to develop treatment tailored to each patient. Progress in personalised breast cancer treatment requires the development of new therapies for underserved breast cancer patients and new tests or biomarkers that can identify the most appropriate treatment for each breast cancer patient.’
Associate Professor Swarbrick studies the biology of triple negative breast cancer to find new treatments for this aggressive disease. He has two areas of interest:
Tumours as ecosystems
Cancers are complex ecosystems in which many ‘normal’ cell types play important roles in tumour growth. With Professor Sandra O’Toole, he and his team have shown that cancer-associated fibroblasts (CAFs) provide a supportive environment that helps triple negative breast cancer cells survive therapy. They are developing ways to block this support to increase the impact of existing cancer therapies.
New drugs that activate the immune system are showing remarkable success in the treatment of some cancers such as melanoma and lung cancer. The results in breast cancer are less dramatic, however approximately 20% of triple negative breast cancer patients do respond to these drugs. Associate Professor Swarbrick and his team aim to uncover what determines whether a breast cancer patient resists or responds to immunotherapy and devise new strategies to sensitise triple negative breast cancer to immunotherapy.
Other areas of investigation
Resistance to anti-estrogen therapies
Estrogen receptors (ER) drive cancer growth in 70% of all breast cancers and drugs that target the ER pathway, such as Tamoxifen and aromatase inhibitors, have been very successful in the management of ER positive cancers. Relapse, however, remains an issue.
"We are seeing that ELF5 may be behind two key features of ER positive cancers when they spread – escape from control by anti-estrogen therapy and metastasis."
Professor Chris Ormandy
Professor Chris Ormandy, Head of the Cancer Biology Laboratory, Dr Samantha Oakes and Dr David Gallego-Ortega are focused on discovering the genetic program that underlies normal mammary development. When these genes mutate or become dysregulated during the initiation of the cancer process, they can continue to influence the characteristics and behaviour of the resulting cancer. As such, these genes provide excellent candidates for new therapeutic targets or prognostic biomarkers.
Professor Ormandy’s Laboratory has discovered a key developmental pathway controlled by a single transcription factor called ELF5. Transcription factors are proteins that read a cell’s genetic code, initiating a program that switches genes on or off. In this case, ELF5 inhibits sensitivity to estrogen very early in the life of a breast cancer cell.
‘ELF5 levels rise in response to the hormones of pregnancy, directing the formation of the structures in the breast that synthesise and secrete milk,’ explained Professor Ormandy. ‘It does this by forcing newly produced cells to adopt a milk-secreting role over other possible paths. These milk-producing cells are also estrogen-receptor negative.’
In breast cancer, ELF5 continues to exert aspects of its normal role, causing cells to lose ER expression – and to proliferate. Anti-estrogen therapies given to treat ER positive breast cancers work by blocking the estrogen signal that drives their growth, but if these cells are able to boost ELF5 levels, like breast cells in pregnancy, they lose the ER, along with their sensitivity to the anti-estrogen drugs.
‘ELF5 has another even more sinister role. It is able to attract cells of the immune system to the tumour, where they have their function subverted and assist the breast cancer cells to metastasise. We are seeing that ELF5 may be behind two key features of ER positive cancers when they spread – escape from control by anti-estrogen therapy and metastasis.
‘We are currently developing ELF5 as a prognostic biomarker in ER positive breast cancer, to predict resistance to antiestrogen therapy and early metastasis. We are also seeking to discover how ELF5 regulates the ER and its transcriptional program, to see if there may be ways to intervene with new drugs to prevent ELF5-driven resistance to therapy.’
Cancer metastasis in bone
Bone Biology researchers are also investigating the bone diseases, including osteoporosis, resulting from common cancers that grow in bone, or spread to bone such as breast and prostate cancer. Research has shown that advanced breast and prostate cancers, which have travelled to the bone and myeloma (a cancer which forms in the bone marrow) have dramatic effects on the skeleton, breaking it down or causing bone to form where it shouldn’t.
"Our research has shown that the bone’s own dynamic process of building up and breaking down bone can send signals to cancer cells inside it, to stay dormant or become active. This has led us to think in a whole new way about treating bone metastasis – and there are two particularly promising treatment approaches."
Professor Peter Croucher, Head, Bone Biology Division
Studies have also revealed that bone acts as a reservoir for dormant cancer cells that, when awakened, cause new active growing cancers that are very difficult to cure, devastating fractures and dramatically worsen the prognosis of cancer patients.
‘Once a cancer spreads to bone, it becomes notoriously difficult to treat,’ said Professor Peter Croucher, Head, Bone Biology Division. ‘There are a great many dormant cells, yet only some of them are activated, and those that are, become activated at different times. So, it’s important to establish exactly what activates those cells in bone. Is it some signal within the cells themselves, or is it a change in their environment?
‘Our research has shown that the bone’s own dynamic process of building up and breaking down bone can send signals to cancer cells inside it, to stay dormant or become active. This has led us to think in a whole new way about treating bone metastasis – and there are two particularly promising treatment approaches.
‘The first is that we could inhibit the breakdown of bone, so as to keep cancer cells in long-term hibernation. In fact, there are already drugs that can do this, such as bisphosphonates (used to protect bone in individuals with osteoporosis), and there’s already evidence that these drugs do improve survival in breast cancer patients.
‘The other, more radical, option is to do the opposite – to wake the sleeping cells by activating the breakdown of bone. Most cancer treatments target active, dividing cells, so waking the sleeping cells should make them susceptible to those therapies – and, ultimately, could eradicate any residual disease.
‘We are now testing these ideas and hope to see them translated into the clinic in the near future. In addition, we have developed some new methods to work out the genes that control these rare dormant cells in bone. We are now looking to block the actions of these genes in order to stop them hibernating in the skeleton.’
Hormone-Resistant Breast Cancer
As 70% of breast cancers are classified as estrogen receptor (ESR1) positive, the majority of patients receive some form of long-term hormone therapy to inhibit the ESR1-signalling network on which their tumours are dependent. Although this treatment reduces the risk of disease recurrence, half of these patients will acquire drug resistance leaving their cancer to spread – to the bone, brain, lung and liver – ruling out surgical intervention in most cases.
"Critically, there are epigenetic modifying drugs that are currently in clinical trials to restore drug sensitivity in other cancers by reversing the epigenetic profile of a drug-resistant tumour. We are looking to repurpose these drugs for patients who are predicted to fail on hormone therapy to extend drug response."
Professor Sue Clark
‘When the tumours become drug resistant there is only the option of alternative hormone therapies or, in some instances, targeted therapies to growth-factor receptors,’ said Professor Sue Clark, Head of the Genomics and Epigenetics Division. ‘Responses, however, are often short-lived with a median survival time from relapse of around two years.
‘Our preliminary work has shown DNA hypermethylation as an underlying epigenetic mechanism by which endocrine sensitivity is diminished in ESR1-positive breast cancers and this will allow us to identify which patients will respond well to hormone therapy, as well as shedding light on the relationship between intrinsic versus acquired resistance in ESR1-positive disease.
‘Critically, there are epigenetic modifying drugs that are currently in clinical trials to restore drug sensitivity in other cancers by reversing the epigenetic profile of a drug-resistant tumour.
We are looking to repurpose these drugs for patients who are predicted to fail on hormone therapy to extend drug response.
‘Those patients with recurrences under hormone therapy can also be profiled as suitable candidates for treatment with DNA demethylation agents, such as Azacytidine and Decitabine, which could extend sensitivity to hormone therapies such as Tamoxifen, providing a multifaceted therapeutic strategy for a significant proportion of poor prognosis breast cancer patients.’
National and International Collaborations
- University of Adelaide, Australia
- Cancer Research UK Cambridge Institute, UK
- University of Cambridge, UK
- Cardiff University, UK
- Chris O’Brien Lifehouse, Sydney, Australia
- Dana-Farber Cancer Institute, Boston, USA
- Monash University, Melbourne, Australia
- Oklahoma Medical Research Foundation, Oklahoma, USA
- Otago University, Dunedin, New Zealand
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Princeton University, New Jersey, USA
- Royal Prince Alfred Hospital, Sydney, Australia
- University of California, San Francisco, USA
- University of Melbourne, Australia
- University of Queensland, Brisbane, Australia
- Weill Cornell Medical College, New York, USA
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.