Using a Multi-omics Approach to Identify Metabolic Vulnerabilities Underlying Therapeutic Resistance in Patients with Melanoma

• Applicant: Dr. Thomas Breakell
• Subject Area: Dermatology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566845358

Our study aims to uncover why some patients experience relapse or do not respond to currently available treatments by examining the metabolic activities within melanomas. Although advances in therapies have dramatically improved patient outcomes, melanoma still kills one Australian every six hours. This project is designed to deepen our understanding of how melanoma cells derive energy, especially concerning resistance to treatments like immunotherapy and targeted therapy. We will employ the pioneering technique of stable isotope tracing to directly analyse melanoma metabolism in patients, which represents a significant advance from traditional pre-clinical models. This approach enables comprehensive insights into how melanoma cells utilize nutrients, specifically through glucose and lactate oxidation pathways. Our goal is to determine if these metabolic activities contribute to therapeutic resistance and explore how they could be harnessed to improve patient outcomes. One of the crucial long-term objectives of this study is to develop biomarkers that can reliably predict patient responses to treatment and identify those at high risk of relapse. By understanding the metabolic profiles of tumours, we aim to stratify patients, forming the basis for more personalized future treatment plans. Identifying metabolic dependencies associated with resistance will guide future research into innovative therapeutics that target specific metabolic pathways, potentially preventing metastasis or aiding in the treatment of advanced-stage disease, especially when disease is resistant to conventional therapy. Our research methodology integrates advanced multi-omic approaches, coupling stable isotope tracing with metabolomics and transcriptomics (both bulk and single-cell RNA sequencing), to investigate the metabolic diversity and adaptations of melanoma cells and their environments. By utilizing resources available at the University of Texas Southwestern Medical Center for advanced mass spectrometry, and conducting all other study activities at Peter MacCallum Cancer Center in Melbourne, we ensure access to essential technologies while maintaining our research focus in Australia. This project aims to contribute meaningfully to the ongoing effort to enhance melanoma treatment strategies. By exploring the metabolic underpinnings of melanoma resistance, we hope to gather valuable insights that can inform future studies in this critical area of cancer research. We believe that this work will deepen our understanding of cancer metabolism and could help to lay the foundation for significant advancements in patient care. Ultimately, our goal is for the findings from this study to serve as a valuable resource for further research, paving the way for improved outcomes for patients with melanoma.

• DFG Programme: WBP Fellowship
• International Connection: Australia
• Host: Professor Grant McArthur