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Current targeted therapies have greatly improved survival rates for breast cancer, but resistance to these therapies is common and is a major cause of death as tumours multiply and spread unchecked.

A/Prof Elgene Lim and others have found that a protein called the androgen receptor may be active in tumours which are resistant to common breast cancer treatments. Androgen receptors are present in the majority of primary breast cancers and in about 75 per cent of tumours that have spread to other parts of the body (metastasised). There are number of new therapies that have been developed to modulate the Androgen receptor.

A/Prof Lim and his collaborators, Prof Wayne Tilley, Prof Jason Carroll and Dr Theresa Hickey, international leaders in the field of hormone receptors, propose that manipulating this receptor will prevent, delay or stop the progression of therapy-resistant breast cancer, providing a new approach to treating these tumours and, in the long term, improve breast cancer survival rates.

More immediately, the project will also seek to identify predictive biomarkers, or gene signatures, that will help select the most appropriate types of breast cancer in which androgen modulation therapy may be evaluated in future clinical trials.

These days 90 per cent of early, localised breast cancers are cured by surgery. However, for 10 per cent of these ‘surgically-cured’ women, their breast cancer will reappear and metastasise (spread to other parts of the body) within five years.

Metastatic breast cancer generally has a poor prognosis as tumour growth is more aggressive and treatment options are rendered ineffective if the cancer spread is well advanced when diagnosed.

Metastasis occurs when solid cancers release cells, called circulating tumour cells (CTCs), into the blood stream which then resettle at distant organs and form more tumours. For a long time many CTCs just stay dormant without growing into a harmful tumour. However, sometimes these cells can wake up and change into rapidly growing tumour cells. This change from dormant cells to metastatic cells is currently not well understood.

In approximately 30 per cent of breast cancer patients who are considered surgically cured, sometimes for decades, CTCs continue to circulate in their blood. These patients are at higher risk of eventual disease relapse and better monitoring techniques could increase their chances of catching metastatic CTCs early.

Associate Professor Therese Becker from The Ingham Institute will explore a gap in knowledge in advanced breast cancer that has the potential to extend breast cancer patient survival and help prevent deaths from metastatic disease.

Her project aims to identify the genes that cause the change from dormant to metastatic cancer cells and to understand potential triggers for the change. This knowledge will have two important potential outcomes for breast cancer patients; it will enable A/Prof Becker’s team to develop a blood test to monitor potentially emerging metastatic CTCs in breast cancer survivors which will help ensure they receive treatment in time, and it could lead to potential avenues for developing therapies that would prevent CTCs from switching from a dormant state into metastatic disease.

Most women with invasive breast cancer have hormone sensitive tumours and are treated with an aromatase inhibitor or tamoxifen. Increasingly women are receiving more than five years of this treatment.

Aromatase inhibitors work by blocking the production of estrogen throughout a woman’s body, therefore depriving any remaining breast cancer cells of estrogen. A little talked about side-effect, common among postmenopausal women with hormone sensitive breast cancer taking an aromatase inhibitor is vaginal dryness, irritation, painful sex and urinary tract problems.

These symptoms can be very severe, and lead to avoidance of sexual activity and relationship distress. As a result, some women stop taking their aromatase inhibitor, and this increases the risk of a relapse.

Although low dose vaginal estrogen, which is the standard treatment for these vaginal symptoms, is sometimes used by women in this setting, it would be highly preferable to be able to offer women an effective non-estrogen alternative.

There is some evidence that a low dose of vaginal testosterone cream might be effective and safe for women taking an aromatase inhibitor.

Professor Susan Davis and her team will conduct a trial to evaluate the effectiveness and safety of intra-vaginal testosterone therapy in women taking an aromatase inhibitor and determine their level of sexual satisfaction and function, as well as objective and subjective measures of vaginal health and urinary incontinence.

This study has the potential to improve the wellbeing and quality of life of a large proportion of women who have had breast cancer. This extends beyond individual women to include their intimate partners and contributing to domestic wellbeing.

Professor Davis hopes that information about the study will facilitate discussion about vaginal and urinary tract issues and will de-stigmatise the intimate issues and encourage affected women to seek help and feel more able to discuss their symptoms with their partner.

Removing the primary tumour via surgery, combined with hormone therapies, chemotherapy and radiotherapy significantly improves patient survival, however once the cancer spreads (metastasises) there are few treatments available. The majority of cancer patients die of their metastatic disease rather than the primary tumour.

Immunotherapies are treatments designed to boost the body’s natural defences to fight cancer, and currently they are one of the few successful therapies for metastatic disease.

Recently, a new generation of immunotherapies (called checkpoint inhibitors) have shown dramatic success in treating metastatic melanoma, but as yet are not overly effective in breast cancer patients.

Developing improved immunotherapy regimes for metastatic breast cancer is imperative, however, the first step is to gain a better understanding of the interactions between metastatic cells and the immune system.

Dr Simon Junankar and his team are using a cutting-edge technique called cellular DNA barcoding to track how cancer cells respond to treatment and determine the factors that allow some cancer cells to avoid the immune system.

Understanding how metastatic breast cancer evades the immune system, and whether new types of immunotherapies can overcome this, will help explain why the current immunotherapies do not work and could open new effective therapeutic avenues.

Cancers that are low in the human epidermal growth factor receptor 2 (HER2), and also lack receptors to the hormones estrogen and progesterone, are called triple negative breast cancers. They generally have poor prognosis, are unresponsive to current treatments and have a high propensity to affect younger women.

Cancers that do express HER2 can be treated with potent anti-cancer drugs called ‘antibody conjugates’ that are effective against tumours while also reducing side effects for the patient.

Kadcyla (also called Trastuzumab Emtansine or T-DM1) is a one such antibody conjugate for women who have HER2 overexpression on their breast cancers. It’s available in Australia and approved for use in the public health system.

Associate Professor Loi’s preliminary studies have shown that triple negative breast cancers that express low levels of HER2 can also respond to Kadcyla, raising the possibility that this existing therapy may be also work for these patients.

If her investigation shows the potential for Kadcyla to be a successful treatment for tumours with low HER2 expression, it could be a new application for the treatment which would have a huge impact on the outcome for the many women with advanced triple negative breast cancers and low HER2.

There have been dramatic improvements in the outcome for those with breast cancer over the past 20 years, and the five-year survival is now nearly 90 per cent. However there remain challenges in diagnosing and treating breast cancer.

These challenges include: how to select which patients are likely to benefit from chemotherapy and those who may be safely spared this toxic therapy; predicting which patients with pre-cancerous breast changes will go onto develop invasive carcinoma and those who don’t need  surgery and or radiotherapy; how to identify novel treatment approaches for rare types of breast cancer.

The common feature among these issues is the ability to select the best treatment for individual patients.  Molecular pathology is an emerging discipline which focuses on the study and diagnosis of disease by examining the molecules within organs, tissues or bodily fluids. This is done using cutting edge techniques, such as advanced genomic sequencing including whole genome sequencing in some cases.

Molecular pathology can play a very important role in better understanding the genetic changes in breast cancers and using that information to help select the optimal treatment for each patient.

In this study, Professor Sandra O’Toole will use these technologies to assess thousands of mutations in cancer genes in breast tumour samples. Her goal is to improve decision-making and treatment options for patients with breast cancer in 3 areas in particular:

  1. Better understanding which types of tumours are more likely to respond to chemotherapy: chemotherapy reduces deaths from breast cancer but it has significant side-effects, and there are few cost-effective tests that can predict which patients are most likely to benefit. Professor O’Toole aims to analyse breast cancer tissues using next generation sequencing from clinical trials to explore predictive tests for whether chemotherapy is likely to be effective.
  1. Understanding why abnormal pre-cancerous cells (called ductal carcinoma in situ) goes onto invasive cancer: Early diagnosis of breast cancer through screening has reduced deaths from breast cancer while also identifying increasing numbers of DCIS that may not always develop into invasive cancer, but which are currently treated with surgery and/or radiotherapy. This study will develop a large collection of DCIS tissues and matched clinical information that can be used to develop tests that may predict which patients need these treatments.
  1. Greater understanding of rare but aggressive types of breast cancer: There are rare but aggressive types of breast cancer, such as malignant phyllodes tumours and metaplastic breast cancer, with few or no effective treatment options if surgery is not successful as they usually do not respond well to chemotherapy or radiotherapy. Professor O’Toole will use new genomic technologies to study these tumours to find new treatment approaches.

One fifth of breast cancers over-express a protein Her2, which promotes cancer. Although treatment of Her2+ breast cancers with Herceptin (Trastuzumab) is a key clinical milestone, many women develop Trastuzumab resistance and their cancers tend to return and spread to other parts of their bodies. Relapse is a major obstacle to effective treatment and patients’ long-term survival.

In a previous pilot study, Professor Ygal Haupt found that a cancer promoting protein, Mdmx, is highly expressed in breast cancers and could be responsible for getting in the way of a key suppressor of cancer, named p53. By targeting the protein Mdmx he was able to reduce the growth of luminal and triple negative breast cancers.

This new study expands the scope of investigation into Her2+ breast cancers. The results could define a new approach to treating the Her2+ breast cancer subtype, which has relied primarily on targeting the Her2 protein.

A number of Mdmx specific treatments are in clinical development, but not in the context of breast cancer. This study aims to establish the suitability of targeting Mdmx for treating Her2+ breast cancer and paves the way for clinical trials.

Professor Haupt believes the treatment will be suitable to most Her2+ patients. Trastuzumab responsive patients are likely to benefit from combined treatment of Trastuzumab and Mdmx targeting. Importantly, even patients with acquired resistance to Trastuzumab are predicted to benefit from an Mdmx inhibitory approach.

In one third of women diagnosed with breast cancer the primary tumour metastasises (spreads) to distant organs, most commonly the bone. Once breast cancer spreads to the bones it is incurable, so there is a critical need for a preventative treatment against bone metastasis.

This research project aims to develop a natural-based and relatively non-toxic agent to reduce the risk and burden of breast cancer bone metastasis, and effectively reduce cancer-related skeletal complications, to significantly increase the life expectancy and quality of life of women with advanced breast cancer.

Curcumin, a potent but non-toxic plant extract (the active ingredient of turmeric) has recently attracted much attention in medicine due to its remarkable therapeutical value, such as anti-cancer, anti-inflammatory and anti-microbial properties.

Dr Rohanizadeh’s team has previously demonstrated that curcumin’s anti-cancer activities are significantly improved when it is formulated into nanoparticles (tiny particles used to deliver targeted treatments). In this project, he intends to extend this research by investigating the combination therapy of curcumin and bisphosphonates.

Bisphosphonates are agents that are well-known for their strong binding affinity to the calcium of the bones and effective slowing of the bone renewal process. This is important for cancer treatment, because slowing the process of bone renewal also slows cancer cell growth. Bisphosphonates are well-tolerated in people and commonly used to treat osteoporosis and as a palliative treatment in patients who have already been diagnosed with metastatic bone cancer.

This is the first time that this type of combination therapeutic agents has been proposed to prevent bone metastasis in breast cancer patients. Preventing breast cancer bone metastasis using these novel bisphosphonate-curcumin nanoparticles has two advantages: i) the nanoparticles will kill breast cancer cells lodged in bone; and ii) they slow the renewal process of bone that attracts and stimulates cancer cells.

If successful, this combination will be safe, effective, natural-based and non-toxic preventative therapy for deadly metastatic breast cancer. It could also prove a popular choice for patients preferring more natural therapies.

The importance of the immune system in breast cancer is increasingly being recognised and a large body of evidence shows that breast cancer patients with high levels of immune cells within the tumour have a good prognosis following standard treatments.

However, in the majority of patients, the immune system is unable to recognise and attack the tumour. This is largely due to the overabundance of a particular population of white blood cells called regulatory T cells (Tregs), which are expanded to unnaturally high numbers by the tumour cells to suppress the immune system and promote tumour growth.

Previous studies have shown that depletion of Tregs in mice dramatically enhances the therapeutic effectiveness of standard cancer treatments such as radiotherapy and chemotherapy. However, it remains impossible to reproduce this effect in patients due to the lack of effective agents able to deplete human Tregs.

This project will develop a novel nanotechnology, called liposomes, to selectively deplete human Tregs and evaluate its therapeutic potential.

These liposomes contain drugs which induce the death of target cells. The liposomes ensure drugs are delivered specifically to target cells (i.e. Tregs) because they are coated with proteins (antibodies) which specifically bind to cell surface proteins expressed only on the target cell.

The team will then assess whether the treatment has inhibited primary tumour growth as well as prevented metastatic spread of the tumour, a vital outcome for patients.

The project also includes investigating another complementary approach using antibody-directed liposomes that can manipulate the ‘master switch’ required for Treg function, and reprogram Tregs from pro-tumour into anti-tumour cells.

This project is the first time this nanotechnology targeting Tregs will be attempted and if successful it could be readily available to breast cancer patients.

Chemotherapy is not able to be used effectively to treat metastatic and triple negative breast cancers because the toxic treatment can’t differentiate between healthy and cancerous cells, and causes harmful side-effects. Usually prescribed doses are not strong enough to completely eradicate the tumours throughout the body.

In this project Dr Pegah Varamini will investigate attaching a ‘carrier’ to the active drug molecule to help it identify the difference between normal and cancer cells and only release the drug inside tumour cells. This modification should allow the dosage to be increased until the tumour is completely destroyed.

Her investigation will look at linking the carrier (LHRH) to a potent anticancer agent (MMAE) which can specifically bind to breast cancer cells and deliver the antitumor agent directly to those cells. This will enhance the efficacy of the treatment and minimises damage to the healthy tissue so there will be a lower risk of relapse and metastasis to other tissues.

The proposed antitumor targeted delivery system will bring hope to the patients who suffer from all types of breast cancer but also the challenging types of breast cancer which have limited treatment options and generally poor prognosis and low survival of breast cancer.

In particular it will be significant in the treatment of triple negative tumours that do not express oestrogen/progesterone/HER2 receptors, and can become resistant to the therapeutic agents that target these receptors.