Grant McArthur lab

The development of both targeted and immune therapies has revolutionized the treatment of advanced-stage melanoma and improved the outcomes of patients. Unfortunately, BRAF/MEK targeted and immune therapies have limitations. Typically, targeted therapies are associated with very high initial response rates, followed by drug tolerance and then tumour progression. In contrast, immunotherapies provide more durable responses but have lower response rates. Targeted therapies can alter the melanoma immune microenvironment, likely making it more amenable to immunotherapy. Thus, combining targeted therapy with immunotherapies might overcome the clinical limitation of the individual classes of therapy and potentially lead to more durable responses and even cure. This study aims to understand therapy-induced time-dependent changes in tumour cells and their microenvironment. Understanding these changes will assist in the development of optimal scheduling strategies for combining targeted and immune therapies. Project Lead: Karen Sheppard

Although newer therapies have improved outcomes for patients with melanoma, we have a limited understanding of why some patients relapse or do not respond to therapy. Understanding the fuels that tumours use to derive energy (metabolism) could help answer such questions. We are using recently developed ground-breaking techniques to study metabolism directly in patients. The two main techniques we will use involve assessing characteristics of the metabolism of a tumour from a standard biopsy sample and administering a non-radioactive, stable isotope infusion of glucose, to get a detailed view of how melanomas utilise this important fuel to aid their growth. Ultimately, we aim to apply the knowledge gained from these studies to predict which patients are likely to relapse and help develop novel therapies for patients with melanoma. Project Lead: Aparna Rao

Excess body weight has been identified as a risk factor for many types of cancers, and for the majority of cancers, it is associated with poor outcomes. In contrast, there are cancers in which obesity is associated with favourable outcomes and this has been termed the “obesity paradox”. In melanoma, recent studies have indicated that increased body mass index improves survival outcomes in targeted and immune therapy treated melanoma patients. The mechanisms underlying how being overweight leads to changes in therapeutic outcomes are not completely understood. Using syngeneic mouse melanoma models, we can replicate the human data showing that fat mice do better on BRAF/MEK targeted therapy than their lean counterparts. Using this model we aim to understand the biological basis for this. In doing so, we will design rational novel therapeutic strategies (targeted, hormonal, immune, metabolic, dietary) that will improve patient outcomes and, importantly, avoid the adverse health effects associated with being overweight. Project Lead: Karen Sheppard

Melanoma is one of the most common cancers in Australia; early-stage melanoma accounts for the largest proportion of new diagnoses. Several patients with early-stage disease develop recurrence after surgical removal of the primary skin tumour, leading to advanced melanoma and death. We are currently unable to predict who will develop recurrence. Utilising novel multi-omic approaches this project will identify the biological factors involved in disease recurrence, leading to improved prognostication and treatment for high-risk patients. This will decrease the likelihood of developing advanced disease at recurrence, improving patient survival and reducing the economic burden of melanoma on the Australian government. Project Lead: Grant McArthur

The response to melanoma treatments varies depending on where the melanoma resides in the body. Interactions between melanoma cells and the organ in which they reside drive changes in these cells. This adaptation of melanoma cells is likely very different in different organs and these differences will alter the response to therapy. Using exciting new single-cell technologies we will trace the changes in individual melanoma cells in response to treatment and as they seed into different body sites such as brain, liver and lung. This will allow us, at the single-cell level, to unravel the complexities of this disease that are associated with these different metastatic sites and response to therapy. This knowledge will aid in our understanding of why in a single patient some tumours respond to therapy and other tumours don’t; it will also guide us on how to best treat tumours at different metastatic sites and how to stop resistance from developing. Project Lead: Karen Sheppard

We have recently identified Protein Arginine Methyltransferase 5 (PRMT5) as a potential new target for CDK4-driven cancers including melanoma, pancreatic and oesophageal cancer. PRMT5 through methylation of histones and many other proteins regulates a diverse array of cellular functions and its activity is regulated by CDK4. Our preclinical studies have identified novel PRMT5 inhibitor combinational therapies that are effective in CDK4-driven cancer models. Using both genomic and proteomic approaches we aim to identify potential downstream targets and pathways that are required for sensitivity to PRMT5 inhibitors and thus potential biomarkers of sensitivity and mechanisms of resistance to this class of inhibitor. In addition, a comparison across melanoma, pancreatic and oesophageal cancer cell lines will provide insight into common and likely fundamental mediators involved in PRMT5 signalling and also those that are unique to each cancer type. Project Lead: Karen Sheppard

Therapy-induced plasticity is a major barrier to curing melanoma patients with targeted anti-cancer therapies. Emerging evidence from our lab suggests that how mRNA is processed and turned into protein underpins melanoma cell plasticity and we hypothesise that if we turn these pathways off, we can prevent therapy resistance. In this project, we are investigating how we can exploit altered mRNA processing to prevent resistance using candidate-based and discovery approaches. For the candidate approach, we are testing currently available and clinically relevant drugs that inhibit mRNA processing, and for the discovery approach, we are applying powerful long-read RNA sequencing technology to identify the full repertoire of mRNA processing events that are induced by therapy. The overall objective of this project is to use this information to identify new combination therapies. Project Lead: Lorey Smith

Melanoma is a highly metastatic cancer however it is difficult to predict which patients with early-stage primary disease will develop metastasis. As melanoma cells metastasize, they undergo a series of cell state transitions that allow them to adapt to different environments in the body. Understanding the molecular features of this process is therefore key to unlocking new biomarkers of disease recurrence and therapies to stop it. We are applying new long-read RNA sequencing approaches to melanoma patient samples to dissect the role of altered RNA processing, and the resultant diversity of mRNA transcripts, in melanoma progression. Understanding this relationship may lead to new biomarkers and therapeutic approaches to stop melanoma in its tracks earlier and prevent recurrence. Project Lead: Lorey Smith