Associate Professor Marina Pajic, Associate Professor Thomas Cox, Dr Sean Porazinski and Dr Amelia Parker

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Medical research will take new leaps as Garvan researchers pursue six new avenues of enquiry thanks to grant support.

Innovative researchers receive grants for cancer and immunodeficiency projects

Six researchers at the Garvan Institute of Medical Research have been awarded grants for their innovative research projects in the fields of cancer and immunodeficiency by Cancer Institute NSW, Cancer Council NSW, and the Job Research Foundation.

Professor Peter Croucher, Garvan’s Executive Director (interim), expressed his pride in the Institute's success in securing the grants, saying, “This is a testament to the excellent calibre of research being undertaken at Garvan and the dedication of our researchers. The environment for research funding is highly competitive in Australia and globally, and these grants demonstrate that our scientists are at the forefront of medical research.”

The grants will fund a range of projects, including the investigation of fundamental cancer mechanisms, the development of new cancer treatments, and the study of Job Syndrome.

A targeted treatment for aggressive lung cancer

Associate Professor Thomas Cox has been awarded a grant by Cancer Council of New South Wales, to design a targeted treatment for aggressive lung cancer over three years. 

Lung cancer development and spread are strongly influenced by the surrounding lung tissue, particularly a mesh-like matrix that holds cells together. In lung cancer, a larger amount of this matrix is produced, changing the behaviour of cancer cells and making the tumour more aggressive. This change in the matrix helps cancer cells spread to other parts of the body and protects them against treatment. 

Associate Professor Cox and his team have identified a molecule in the lung tissue matrix called ‘Collagen IV’, which controls the behaviour of lung cancer cells. It may be useful as a biomarker for patients that have aggressive disease that need more treatment, or as an indicator that those who have the cancer are more likely to have recurrence. By targeting Collagen IV, it may be possible to slow down tumour growth, reduce cancer spread, and improve chemotherapy efficiency.

“Unlocking the secrets of lung cancer is like solving a complex puzzle, and we're excited to have found a key piece in Collagen IV. Once you open up the biology of lung cancer and understand what’s going on, you can work from that understanding of disease progression and design ways to target key molecules,” says Associate Professor Cox.

The ultimate goal is to design a new personalised treatment approach for aggressive lung cancer.

Since other cancers, such as pancreatic and breast cancer, produce a high quantity of the mesh-like matrix, the team's research could have broader impacts on other cancers in the future.

Dr Amelia Parker, Senior Research Officer in Associate Professor Thomas Cox’s Matrix and Metastasis Lab, has been awarded a prestigious Cancer Development Fellowship from the Cancer Institute NSW, which is the highest fellowship award given by the institute to support emerging elite researchers. She will investigate new and more effective treatments for lung cancer patients. 

Lung cancer is a complex disease with many subtypes, each with unique characteristics, making it challenging to develop effective treatments that work for all patients. Additionally, it is often diagnosed at an advanced stage, making it more difficult to treat.

With the limited treatment options currently available, this project will focus on boosting the effectiveness of chemotherapy by reversing changes in the tissue surrounding lung cancer tumours. This will enable the treating team to identify the most effective approach for each patient from the outset.

As well as providing better, more personalised therapy for patients, the aim is to reduce the negative psychological impact of waiting to see if a tumour will return.

“The support of this fellowship will provide a critical foundation for my research and progress in improving lung cancer treatment. It will enable me to identify which patients are at high risk of developing aggressive lung cancer, and what the most effective treatment for them may be,” says Dr Parker.

Taking down the barrier around pancreatic cancer cells

Pancreatic cancer is one of the deadliest cancers worldwide, with a low survival rate – less than 10% after five years – due to its molecular complexity and the challenge of penetrating the fibrous barrier that protects tumours.

Associate Professor Marina Pajic and her research team have identified a cancer-promoting molecular pathway that controls communication between pancreatic cancer cells and stromal cells, a diverse group of cells that provide a supportive framework for the tissues and organs in which they reside.

This pathway is overactive in more than a third of pancreatic cancers, driving the development of the fibrous scar tissue that protects the tumour from chemotherapy.

In response, the team has developed a new approach to target this pathway in combination with chemotherapy, disrupting the communication between the cancer and stromal cells, and disabling pancreatic cancer's defences.

“We’ve identified a hidden pathway to take down the fibrous shield that protects cancer cells, giving chemotherapy a chance,” says Associate Professor Pajic.

Supported by a three-year grant from Cancer Council NSW, her goal is to test different strategies for targeting this pathway in combination with chemotherapy in pre-clinical studies, with the hope of developing a new personalised treatment approach for pancreatic cancer. By tailoring treatment to each patient's molecular or genetic makeup, the team aims to maximise treatment efficacy while minimising side effects.

The project's impact could be significant, with the potential to improve treatment outcomes for more than a third of pancreatic cancer patients.

Developing a new combination therapy for pancreatic cancer

Dr Sean Porazinski, Group Leader in Associate Professor Pajic’s Personalised Cancer Therapeutics Lab at Garvan, was also awarded a prestigious Career Development Fellowship from the Cancer Institute NSW. He will investigate the use of an antifungal medication to enhance the effectiveness of immunotherapy for pancreatic cancer.

The microenvironment around pancreatic tumours suppresses the immune system, allowing tumour cells to evade immune cells – this is why immunotherapy has not worked well for pancreatic cancer.

Dr Porazinski’s team has discovered that the antifungal drug can change the composition of the immune cells surrounding the tumour, switching them from being tumour-promoting to tumour-suppressing, and encouraging ‘killer’ T cells to enter and destroy cancer cells.

“There are cells in the human body that can kill cancer cells, but it’s a matter of getting them into the tumour environment and blocking their deactivation. We plan to use the antifungal to modify the microenvironment. Combined with the right type of immunotherapy, this could allow the body’s immune cells to do their job,” says Dr Porazinski.

The team will perform single-cell sequencing of animal models of pancreatic cancer to understand the immune changes in antifungal-treated tumours and develop the most effective treatment regimes. They will also study immune changes in animal models with intravital imaging through the 

The ultimate goal of this research is to develop new treatment approaches, combining the antifungal drug and immunotherapy, that can be applied to pancreatic cancer and potentially other cancers as well. The researchers will identify biomarkers to determine which pancreatic cancer patients will be most suitable for this therapy approach, with the aim of progressing to clinical trials in the next two years.

Pre-empting resistance to chemotherapy in triple-negative breast cancer

Chemotherapy is a frontline treatment for cancer, but in some cases the cancer cells become resistant to the treatment, making it less effective.

Dr Beatriz Perez San Juan and her team in Associate Professor Christine Chaffer’s lab have discovered that a protein called ZEB1 drives this change in cancer cells. They also found that a process controls how ZEB1 moves around inside cells and influences cancer cell behaviour. Thanks to a three-year grant from the Cancer Institute of NSW, the researchers will investigate if they can 'gate’ ZEB1 to prevent the change in cancer cells and pre-empt any resistance to chemotherapy.

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Triple-negative breast cancer, an aggressive subtype of breast cancer diagnosed in 20–25% of cases, is the main focus of the study. Chemotherapy is only effective in around a third of patients with this type of cancer, and there are currently no targeted therapies available.

“We hope to create the framework for the development of a new drug to treat chemotherapy-resistant cancers and improve survival rates. If the project is successful, this new approach could lead to the development of targeted therapies for patients who currently have limited treatment options,” says Dr Perez San Juan.

Investigating Job Syndrome, a rare immunodeficiency disorder

Professor Stuart Tangye has been awarded a grant by the Job Research Foundation (USA) to study Job Syndrome, a rare immunodeficiency disorder that affects around one in 1,000,000 people.

Over two years, Professor Tangye will study immune dysregulation in Job Syndrome, with a specific focus on its cellular mechanisms and related lung disease.

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Job Syndrome, also known as Autosomal Dominant Hyperimmunoglobulin E Syndrome, is caused by a variation in the STAT3 gene, which is responsible for many functions of immune cells and non-immune cells in the body, including cell growth and division, antibody production and host defence against infections.

People with Job Syndrome have partial STAT3 deficiency, leading to multisystem symptoms, such as recurrent 

 abscesses, a fungal infection called candidiasis and impaired B cell and T helper cell function. The grant will support Professor Tangye's research to identify the mechanisms behind these problems, which could ultimately lead to better treatments for patients with Job Syndrome.

“It's only by understanding the intricate dance of cellular mechanisms in this rare disorder that we'll uncover new ways to treat the diverse impacts of partial STAT3 deficiency, from recurrent infections to lung disease. The Job Research Foundation has given my team the gift of time to dive deep into these cellular intricacies, and for that we are profoundly grateful,” says Professor Tangye.