Author Identifiers

Michael Edward Clark
ORCID: 0000-0002-9748-5221

Date of Award

2021

Degree Type

Thesis

Degree Name

Doctor of Philosophy

School

School of Medical and Health Sciences

First Advisor

Associate Professor Elin Gray

Second Advisor

Associate Professor Katie Meehan

Third Advisor

Dr Jason Waithman

Fourth Advisor

Dr Tarek Meniawy

Fifth Advisor

Dr Leslie Calapre

Abstract

Metastatic melanoma is the third most common cancer in Australia with global incidence increasing. After decades without effective systemic treatments for advanced melanoma, the advent of targeted and immune therapies has substantially improved patient survival. While this is encouraging, further research is needed as the majority of patients treated with targeted therapy ultimately develop drug resistance. Immunotherapy can achieve durable responses in many patients however, not all patients respond to current single or a combination of immune checkpoint inhibitors. Considering the cost and potential toxicities to patients being treated with these therapies, there is an urgent need to develop biomarkers that can predict patient response to treatment, likelihood of toxicity, and ultimately survival. Extracellular vesicles (EVs) are small particles that contain a diverse array of molecular cargos that represent the cell of origin. EVs have established roles in various hallmarks of cancer, including the mediation of drug resistance and immunosuppression. In addition, EVs have tremendous potential as biomarkers to predict or monitor patient outcomes. This thesis aims to provide a foundation of methodologies to explore the potential of melanoma derived EVs. In turn, this will allow an expansion of our understanding on the role of melanoma derived EVs on therapeutic outcomes. Chapter 1 of the thesis provided a review into the development of melanoma, current treatment strategies, drug resistance and a broad introduction on EVs. Chapter 2 demonstrated the ability to detect the mRNA of BRAF splicing variants in the plasma of melanoma patients who developed resistance to targeted therapy. Further, it showed that these mRNA variants were detected in plasma derived EVs. In Chapter 3, the potential of EVs to transfer resistance to BRAF inhibition was explored utilising a panel of BRAF treatment resistant cell lines. However, no evidence was found that EVs could transfer BRAF resistance. In Chapter 4, the plasma of melanoma patients being treated with pembrolizumab was used to isolate EV-RNA to identify a transcriptional signature predictive of response. Lastly, Chapter 5 provides a general discussion of the studies presented in this thesis. Altogether, the results of these studies underscore the potential of EVs as unique biomarkers to predictive response to treatment in melanoma.

Access Note

Access to Chapters 3 and 4 of this thesis is not available.

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