Can a ‘liquid biopsy’ be used to measure response to immunotherapy in patients with non-small cell lung cancer?

2018 Spore Grant winner: Dr Arutha Kulasinghe

Lung cancers are a leading cause of cancer-related deaths in Australia, approximately 12,500 new cases are diagnosed annually. The majority of lung cancers are non-small cell lung cancer (NSCLC), which is often diagnosed at advanced stages, with poor prognosis and often with metastasis to multiple organs.

For patients with NSCLC, treatments that modulate the immune system (immunotherapies) are provided predominantly in the second line setting, after chemotherapy has failed.

In a subset of NSCLC patients, immunotherapies have been shown to achieve significant and long lasting benefits compared to conventional therapies. In particular, this has been demonstrated with checkpoint inhibitors, a type of immunotherapy that can take the ‘brakes’ off the immune system, so that cancer cells can be recognised and killed.

However, these treatments are not suitable for all patients, and are costly, so it is important to identify which patients would benefit most - before starting, and over the course of treatment. The traditional approach using lung tumour biopsy is invasive, associated with many risks, and is often not possible due to tumour location. Therefore, alternative methods to sample the NSCLC tumour tissue are needed.

Dr Kulasinghe’s project will focus on validating a non-invasive, liquid biopsy solution to monitor response to immunotherapy using patient blood samples. The blood samples, containing circulating tumour cells and tumour DNA, will be analysed to monitor for key genetic mutations during the course of treatment.

Overall, the aim of this project is to identify biomarkers that can be measured via liquid biopsy to predict the response to immunotherapy, and monitor treatment response.

This project brings together a multidisciplinary team of clinicians and scientists from TRI partner institutions - Princess Alexandra Hospital, the Institute of Health and Biomedical Innovation at Queensland University of Technology, The University of Queensland Diamantina Institute and industry partner Agena Biosciences. This collaborative team bridges both cancer and immunology, working together towards a precision medicine approach for treatment of NSCLC.

Theranostic biomolecules: Towards a more targeted approach to pancreatic cancer treatment

2018 Spore Grant winner: Professor John Hooper

With a dismal five-year survival rate (~8%), pancreatic cancer was the cause of 2,915 deaths in Australia during 2017. The most common type of pancreatic cancer, pancreatic ductal carcinoma (PDC) is a particularly aggressive form that is associated with high rates of mortality.

While surgery is the only possible curative treatment, ≥80% of patients are ineligible because their cancer has spread. Therefore, there is an urgent need to improve the diagnosis and treatment of PDC.

Over the last decade, radio-labelled biomolecules (peptides, antibodies and antibody fragments) have been used to both image and treat cancer – including pancreatic neuroendocrine tumours, and more recently, prostate cancer.

This ‘theranostic approach’ uses selected biomolecules that are predominantly expressed on the surface of cancer cells. These radio-labelled biomolecules are then used in medical imaging studies to determine the extent of the patient’s disease, and then used to deliver a therapeutic dose of radiation to the patient.

Professor Hooper’s project aims to identify, develop and evaluate potential theranostic approach for patients with PDC. This will be based on identifying biomolecules that are selectively expressed on the surface of PDC cells, and associated with poor prognosis, using a machine-learning bioinformatics approach to narrow down suitable candidates. Then, patient tumour samples will be analysed to determine selective expression of these biomolecules on the PDC cell surface.

If suitable biomolecules can be identified for PDC, a theranostic approach can be developed to improve the diagnosis and treatment of PDC, to help patients with this deadly disease.

This project, which has also been generously supported by the Avner Pancreatic Cancer Foundation, involves a multidisciplinary collaboration of researchers and clinicians from the Mater Research Institute, The University of Queensland, Royal Brisbane Women’s Hospital, the Princess Alexandra Hospital, Mater Hospital, Queensland University of Technology, and the TRI, along with the key industry partner CSIRO Probing Biosystems Future Science Platform.

Can probiotics be used to effectively treat constipation by targeting the gut microbiome?

2018 Spore Grant winner: Professor Gerald Holtmann

Constipation is a common and debilitating problem, with just over one-third of the Australian population reporting more than two constipation symptoms in the past three months.

Although there are many treatments for constipation on the market, they often provide only short-term solutions, and more than half of patients are dissatisfied with current treatment options. As a result, patients with persistent constipation experience reduced quality of life, increased psychological distress and in some cases, increased mortality.

For some patients, their constipation is classified as ‘slow transit’ – a result of a slow transit of waste through the colon, which has been linked with excessive production of methane gas by gut microbes.

Evidence suggests use of treatments that target the gut microbiome may help to improve symptoms of slow transit constipation. Some clinical trials have shown certain probiotics can improve stool frequency in constipation, and have an effect on the gut microbiota, but not all studies agree.

To date, the effect of probiotics on gut microbiota in constipation remains poorly understood, and the role of methane production in these responses is unknown.

Professor Holtmann’s project will investigate whether probiotics can be used as a treatment to improve symptoms of constipation and levels of methane production, in a cohort of patients attending a gastroenterology outpatient clinic in Brisbane.

This single-centre, randomised, double-blind controlled study will involve patients assigned to placebo, or different doses of a patented mixture of probiotic strains.

In addition, this study will also help to determine whether a low-cost diagnostic test such as the hydrogen breath test (used to measure hydrogen and methane) could be used to support the translation of probiotics as a viable treatment option for suitable patients with slow transit constipation in clinical practice.

This multidisciplinary project involves a collaboration of researchers and clinicians across Metro South Health (Princess Alexandra Hospital) and The University of Queensland, with Servatus Ltd as an industry partner.

Can we use ‘inflammatory signatures’ to improve diagnosis of inflammatory skin rashes?

2018 Spore Grant winner: Professor H. Peter Soyer

Many patients are admitted to Emergency and other hospital departments each year with moderate-to-severe inflammatory skin rashes. Although most rashes are benign, certain forms - particularly drug-induced severe skin reactions - can be life threatening if they are not rapidly diagnosed and treated.

Rashes may be caused by multiple factors, including systemic drug reactions, viral or bacterial exanthemas (widespread rash), atopic dermatitis, or generalised contact dermatitis.

Determining the cause of a moderate-to-severe inflammatory skin rash has an immediate impact on choosing the most appropriate treatment approach. It is often difficult to identify the cause of an inflammatory skin rash using conventional tissue microscopy, as many rashes are visually indistinguishable from one another.

However, there is evidence to suggest that these rashes may have different ‘inflammatory signatures’ characterised by varying expression of different immune receptors and proteins.

Professor Soyer’s project focusses on establishing a rapid, highly sensitive diagnostic method to detect these inflammatory signatures in human skin, and assess whether it can be used to determine the cause of inflammatory skin rashes.

If successful, these results will be the first step to developing a test or device that provides an attending physician with a rapid and accurate diagnosis of a moderate-to-severe inflammatory skin rash, enabling rapid and appropriate medical intervention.

This project involves a multidisciplinary collaboration between researchers and clinicians at Metro South Health (Princess Alexandra Hospital), The University of Queensland, Mater Research Institute and with the industry partner XING Technologies.