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Metastasis, the spread of cancer from the primary site in the breast, remains the principal cause of mortality among people with cancer. Breast cancer cells often travel to the lymph nodes before reaching distant organs, where they are believed to grow and adapt, aiding their spread throughout the body. People with cancer present in the lymph nodes face a significantly higher risk of the disease spreading to other organs and recurring after treatment. As a result, lymph node involvement remains one of the most critical prognostic indicators of disease progression. Moreover, immune responses that fight cancer and respond to immunotherapy treatments reside in the lymph nodes. However, the spread of cancer cells to lymph nodes can suppress this anti-cancer immunity.

Previous research by Professor Scott Mueller from the University of Melbourne and the team has shown that as cancer cells invade the lymph nodes, they disrupt healthy fibroblasts—cells essential for initiating effective immune responses—thereby hindering a person’ ability to respond to current immunotherapies.

In this NBCF-funded study the team aims to generate new knowledge about how lymph nodes participate in breast cancer progression. By using state-of-the-art laboratory models of metastasis, and analysing tissue samples from people with breast cancer , they aim to uncover the cellular pathways and molecules responsible for the disruption of lymph nodes function by cancer cells. The team will explore whether targeting these pathways can restore immune activity and evaluate the potential for combining these approaches with existing immunotherapies to enhance treatment outcomes.

Mucinous ovarian carcinoma (MOC) is a rare subtype of epithelial ovarian cancer, making up approximately 2-3% of cases. There are various forms of MOC that can behave differently, however there is still much unknown about this rare subtype. MOCs don’t respond well to current treatments, meaning discovery of new treatment options is critical. 

A/Prof Gorringe’s lab is one of the only in the world with a dedicated MOC research program. Recently, they were awarded a National Health and Medical Research Council grant to investigate the cell of origin for MOC, as currently its cause and origins remain unclear. Despite the lack of clarity on why MOC tumours occur, OCRF funding will enable the team to find out how to stop it and identify new treatment approaches.

Breast cancer is the most common cancer among women in Australia, with over 21,000 new cases each year. About 70% of people with breast cancer have Estrogen Receptor Positive (ER+) cancer that responds to endocrine treatment. However, for about 30% of these people, the cancer eventually stops responding to treatment and spreads (metastasizes). Inhibitors of Cyclin-Ddependant Kinases 4 and 6 (CDK4/6i) are now standard of care treatment of metastatic ER+ breast cancer. However, treatment failure can develop and there are no effective second-line treatment strategies.

The work of Dr Achinger-Kawecka (The University of Adelaide) and others suggest that resistance to CDK4/6i may be caused by “jumping genes” – also known as Transposable Elements (TEs). These are pieces of ancient viral DNA that currently make up nearly half of our genome. Once thought to be inactive, TEs are now understood to play an important role in cancer by switching on genes that help tumours grow and resist treatment.

Dr Joanna Achinger-Kawecka and colleagues have also shown that activating a key tumour suppressor protein known asp53, could be a promising avenue for overcoming resistance to CDK4/6 inhibition. In this NBCF-funded study they will use preclinical models derived from tumour samples of ER+ patients who relapsed on CDK4/6i therapy to provide evidence that p53 activating drugs can turn off these oncogenic jumping genes and restore treatment sensitivity to CDK4/6i therapy.

Metastasis—the spread of cancer around the body—is responsible for all breast cancer deaths. About 30% of ER+ breast cancer cases progress to metastatic disease, largely due to resistance to CDK4/6i, the standard –of care treatment. Currently, no clear second-line treatment strategy is available for patients who develop resistance to CDK4/6i. As a result, the growing prevalence of CDK4/6 inhibitor resistance is set to become a significant challenge in managing metastatic ER+ breast cancer.

Dr Nicole Campbell is investigating how a protein naturally produced by the body, interferon epsilon (IFNε), could be harnessed as an effective immunotherapy to better treat high-grade serous ovarian cancer. This approach aims to target ovarian cancer cells that have metastasised (or spread), or that are resistant to currently available treatments.  

Because many cases of ovarian cancer are diagnosed in the later stages, when the cancer has spread, the likelihood of it coming back, or recurring, after initial treatment is high and therefore this research could provide an important new treatment option for metastatic or recurrent ovarian cancer. 

Among the recognised risk factors for breast cancer, a strong association has been observed between delayed childbirth or not having children at all. Previous research by Associate Professor Kara Britt and the team found that in the breast of women who had never had children had changes in their fibroblasts of a certain protease normally only known to have a role in the blood. The levels of this protein were higher in the breast tissue of those women that had given birth. In addition, lower levels of this protein were linked to poorer outcomes. The protein does not have any known roles in the breast or in cancer development but is well known for its role in controlling processes involved with repairing wounds. Tumours have often been referred to as wounds that never heal. Hence, regulating the levels of this protease could serve as a preventative therapy for women at increased risk of breast cancer.

In this NBCF-funded study the team will collect samples from normal, early stage and invasive breast cancer from women having surgery and assess how this protease is working. Drugs that currently impact the levels of the protease are already used safely in people for blood disorders. Hence, breast cancer laboratory models will be used to evaluate if this drug or related drugs have the potential to be repurposed as a precision breast cancer precision therapy or preventative treatment for breast cancer.

Patients with aggressive breast cancers, including those with large tumours, high-grade triple negative or HER2 positive breast cancers are at high risk of treatment resistance and of the cancer returning after treatment, leading to poor survival outcomes. These patients often receive therapy before tumour removal (termed neoadjuvant therapy) aimed at reducing the size of the cancer prior to surgery. Currently, there are few biomarkers to predict which patients will respond to neoadjuvant therapy and those that will not, and response to neoadjuvant treatment is an indicator of patient outcome.

This project, led by Dr Amy McCart Reed (University of Queensland), will use cutting-edge genomic techniques to identify markers of treatment response or resistance. The study also aims to identify the most effective genomic technology, for personalised medicine, to profile individual tumours to match patients with the best therapy.

The spread of breast cancer to the brain is a major cause of mortality for patients with triple negative breast cancer (TNBC). In this study Prof Kum Kum Khanna (QIMR Berghofer Medical Research Institute) will examine whether Auranofin, a drug proven to be safe for the treatment of rheumatoid arthritis and can cross the blood-brain barrier, can be repurposed for the treatment of metastatic TNBC. Auranofin will be tested in combination with other FDA approved anti-cancer drugs known to reach the brain to identify new combination therapies for the treatment for metastatic TNBC.

Metastasis is an incurable spread of cancer and is the main cause of cancer death. It is evident that metastatic cancers differ from the primary tumors from which they originate. Yet, much is unknown about how breast cancer spreads.

One of the main challenges in understanding cancer metastasis is a lack of access to tissue from people with advanced disease.

In this NBCF-funded study, Dr Zhi Ling Teo will use a unique tissue bank that has been established at the Peter MacCallum Cancer Centre to trace the full lifecycle of aggressive HER2+ breast cancer. In particular, her study will focus on changes in the immune system over the course of the disease and how this affects outcomes. 

Overall, the study will provide new information on ways to anticipate, inhibit or suppress the evolution of drug resistance and metastasis in HER2+ breast cancer.

Estrogen receptor positive breast cancer is the most common cause of breast cancer, affecting up to 80% of female and 90% of male breast cancer patients. In ER+ tumours, the hormone estrogen fuels the growth of the cancer. Current treatment options aim to either block the estrogen receptors, or lower the levels of the estrogen hormone in the body, to starve the tumour of its fuel. However, this treatment also leads to estrogen deprivation in the rest of the body, which can lead to side effects.

This study, led by Dr Amy Dwyer from the University of Adelaide, will trial a completely new treatment strategy. Instead of eliminating estrogen receptor activity, the team will test therapies that reprogram the estrogen receptor to prevent the growth of tumours but retains activities needed by the body.

The project will trial drugs that are already on the market, which have been shown to modulate estrogen receptor activity. There will likely be additional benefits to these new treatments, including promotion of bone and muscle health, increased libido and prevention of hot flushes. The hope is that this new approach may be able to treat women with breast cancer, without making them feel miserable in the process.

Chemotherapy is well known to have off-target adverse events, such as cardio-toxicity, or damage to the heart. This can lead to cardiovascular disease later in life, which is now a leading cause of death among breast cancer survivors.

It is possible to reduce the risk of cardiovascular disease through specialised exercise rehabilitation. This is usually provided in supervised clinic-based programs, but these can be challenging to access for women due to time, travel and cost barriers. Home-based alternatives have not been as effective. 

Tele-rehabilitation could bridge the gap – enabling direct supervision by a clinical exercise specialist while the participant completes the therapy in their own environment. 

This approach has previously been shown to be effective for people with coronary heart disease, and this will be the first time it is used with women who have previously had breast cancer.