Repurposing an old drug

Recent advances in immunotherapy have shown unprecedented efficacy and improved survival of patients with metastatic melanoma. Nevertheless, still, a large population, estimated at around 50% of metastatic melanoma patients, do not benefit from immunotherapy.  In the past decades, metabolism has become a hallmark in cancer. In melanoma specifically, it was linked to immunotherapy resistance. A  high glucose uptake and lactate production is a commonly shared trait in melanoma. Lactate contributes greatly to the acidification of the tumour microenvironment (TME) and confers an immunosuppressive TME that leads to attenuated immunotherapy responses. Modulating metabolism to lower lactate production and thereby reverting the immunosuppressive TME might be a promising line of study to enhance the efficacy of immunotherapy in metastatic melanoma patients. As a proof-of-concept, a 13C-tracer-based clinical trial is planned with dichloroacetate (DCA) to repurpose and validate its use to lower lactate metabolism in melanoma patients. DCA redirects the lactate precursor into mitochondrial metabolism, thus preventing excessive lactate production.  The analysis of 13C-tracer enrichment allows for direct insight into the active metabolic processes, contrary to the quantification of metabolite concentrations alone. It is important to realise that many challenges lie ahead for the implementation of DCA as a standard in melanoma therapy. Amongst these challenges is the unmet need for tools and markers to monitor and predict the response of melanoma metabolism to DCA, and more specifically to determine how patient-specific metabolic phenotypes affect this DCA response. In this thesis, I aimed to meet these challenges and present data and the developed methods that lay the groundwork for interpreting pre-clinical and clinical data, studying melanoma metabolism,  and monitoring and predicting drug response in vivo in melanoma.

Dissertation: http://hdl.handle.net/11370/3ee64721-46ee-4563-ad7f-806ebbdf2927