2022 Cancer Council WA Research Project Grants

Breast cancer (BC) is the most frequent cancer in women. While most BCs expresshormonal receptors (HRs) and have excellent responses to anti-estrogens (anti-E2s), asubset of HR positive (HR+) BCs are more aggressive, making them treatment resistant andlikely to return. Currently, there are no tests to distinguish these high-risk HR+ BCs fromthose that will respond to anti-E2s. We propose that these patients can be identified bydetection of a new cancer-driving gene (Adipogenesis Associated Mth938 DomainContaining, AAMDC), found at very high-levels in these BCs. We discovered that theAAMDC protein made by the gene is a new actor that drives BC by turning on a growthsignal called the mTOR pathway. We will develop a test to diagnose these patients bymeasuring the levels of AAMDC, and then test anti-AAMDC drugs (such as mTOR-blockers)in combination with anti-E2s. This work will produce tests and therapies ready to use inclinical trials to better treat these aggressive tumours.

To ensure that signals from outside the cell lead to into appropriate cellular responses, the signalling inside the cells is highly regulated. Inside the cell, a group of molecules that communicate with each other to control these responses is called a signalling pathway. The PI3K group of molecules are the most active in breast cancer (BC). Approved chemotherapy drugs targeting the PI3K pathway demonstrate that patients having alterations in the PI3K molecules show decreases in tumour growth. However, the number of patients who improve on these drugs is low because somehow the pathway is getting reactivated even when chemotherapy is given.
This proposal seeks to understand why in some patients the pathway remains on and to identify patients beforehand who are most likely to benefit from these drugs. We are also designing new chemotherapy drugs that may be used in combination with those that target the PI3K pathway to see if we can increase the number of patients surviving this disease.

Whilst overall survival rates have vastly improved for acute lymphoblastic leukaemia, some subtypes and patient groups still have poor outcomes with less than a 50% chance of survival. Harnessing an individual's immune system to fight cancer has been successful for some, however not all patients are healthy enough to have their own cells harvested. This means there is a great need for an alternative approach.
Our solution is to use the cancer killing immune cell, the natural killer (NK) cell, with the benefit being that they can be collected from healthy donors and prepared long before required. We have identified that some NK cells are superior at eliminating leukaemia and have utilised genetic technology to understand why they perform better. Using this information we will further enhance and refine the cancer killing capabilities of these cells. Our goal is to be able to create a scalable ‘off the shelf' immunotherapy to ensure all patients can receive this life-saving treatment.

Every year more than 300,000 women are diagnosed with ovarian cancer worldwide. Ovarian cancer claims lives of more than half of affected women within just 5 years after their diagnosis. This is because ovarian cancer is mostly detected at late stages and typically becomes resistant to the current standard treatment, even after initially good response.
Treatment often fails because an ovarian tumour is made up of many different types of cancer cells. Some types of cancer cells may be killed by the standard treatment, while others turn out to be resistant and cause the tumour to grow further.
Here we will study how resistant cancer cells that are present before treatment may explain chemotherapy resistance and recurrence. To study this we will grow slices of patient's tumours in the lab and treat them with various chemotherapy drugs. The findings of this study may be used in the future to make tumours more sensitive to treatment and the improve outcome of women with ovarian cancer.

Immunotherapy has generated great excitement, yet offers durable effects in only a minority of patients. For breast cancer patients immunotherapy is not available in Australia because of its limited effectiveness. Part of the problem is that immune cells cannot reach the cancer core in sufficient numbers to stop its growth. Our goal is to improve currently available immunotherapies by helping immune cells to "invade" deep into the cancer and destroy it. We will do this by using drugs which transform cancer blood vessels - which are highly abnormal and chaotic - into a shape similar to normal blood vessels. We will use preclinical breast cancer models and specimens collected from participants of a clinical trial to explore how our selected drugs enhance the response to immunotherapy. We expect that bringing more immune cells into tumours will increase the overall response rate to immunotherapy.

New treatments that activate the immune system have improved the survival of a proportion of melanoma patients. However, there is an urgent need for tests that can guide who will respond to these treatments. The proposed study will use new technologies to develop blood tests that can provide oncologists with critical information about the tumour to optimise treatment, improve response rates and reduce unnecessary exposure to toxic treatments.

Liver cancer is a major health challenge on a global scale that has a significant economic and social burden on the community. With rapidly increasing numbers of liver cancer cases and critically low survival rates for patients, new therapies are urgently required. The aim of our research is to deliver our new anticancer drug directly to the liver for the targeted treatment of liver cancer. The global effort to produce an effective vaccine against COVID-19 has benefited medical research with major advances in drug development and targeted delivery. We have designed a new drug that kills liver cancer cells in the laboratory, and by using the same innovative COVID-19 vaccine technologies, we aim to deliver this drug directly to liver tumours. If successful, we will fast-track the drug for clinical use to treat people with liver cancer. This new breakthrough will improve treatment effectiveness, reduce serious side effects and importantly, extend people's lives.

Acute leukaemia is the most common type of cancer seen in children (15 to 20 new cases each year in Western Australia). Although treatments and outcomes have improved remarkably, leukaemia remains the second highest cause of death by cancer in children. Furthermore, many children still suffer from treatment toxicity or develop relapse. These clinical features are exacerbated in children with Down syndrome (DS), a community that already have higher risks of leukaemia compared to other children.
This study aims to test a new therapy targeting the leukaemia cells that are resistant to current treatments and are responsible for relapse. We will use animal models uniquely available in our lab to combine this new therapy with the standard treatments used in clinics. Outcomes from this study are intended to provide to clinicians with new tools to better track and destroy these resistant cells, to improve the quality of care and long-term survival of West Australian children with leukaemia.