Background/Aim
There is increasing interest in altered metabolism in melanoma in the context of disease progression and therapeutic resistance, yet many of the pivotal studies have been conducted in pre-clinical models. The MetaMel Study (NCT05570227) is a prospective clinical trial that enables stable isotope tracing to characterise melanoma glucose metabolism. The overarching objective is to understand and define tumour metabolic phenotypes underpinning therapeutic resistance in patients with melanoma and to identify metabolic biomarkers and therapeutic options. Initial analyses aim to define inter‑tumour metabolic heterogeneity and assess whether mass-spectrometry features associate with intrinsic clinical and molecular tumour features.
Methods
In this investigator-initiated study at the Peter MacCallum Cancer Centre, commencing August 2023, patients with melanoma undergoing standard‑of‑care surgical resection receive a peri‑operative intravenous bolus of [U‑¹³C]glucose followed by continuous infusion prior to excision. Blood and tumour samples are collected for mass spectrometry analysis of ¹³C incorporation into glycolytic and tricarboxylic acid cycle intermediates. Tumour metabolic activity is evaluated using ratio‑based isotopologue measures. These include citrate m+2/pyruvate m+3 as a surrogate of mitochondrial glucose oxidation and tumour/plasma glucose m+6 to account for systemic delivery. Ratios are correlated with key clinicopathologic characteristics.
Results
With ongoing recruitment (target n=120), [U‑¹³C]glucose infusions have been performed in 14 patients (4 BRAF-mutant, 5 NRAS-mutant, 4 triple-wildtype, 1 not determined; 2 primary melanomas, 7 lymph node metastases, 3 in-transit metastases, 1 soft tissue, 1 small bowel metastasis; 8 with prior ICI-therapy, 6 no prior systemic therapy). [U‑¹³C]glucose infusions were feasible and well tolerated, achieving steady‑state circulating labelled glucose without safety signals. Analysis reveals pronounced inter‑tumour variability in tumour glucose delivery, utilisation, and downstream metabolic fate. Substantial differences are observed in the balance between glycolytic labelling and mitochondrial glucose oxidation, reflected by variation in pathway‑level metabolic ratios across tumours.
Conclusions
The MetaMel Study demonstrates the feasibility of applying in vivo [U‑¹³C]glucose tracing to directly interrogate human melanoma metabolism and highlights inter‑tumour metabolic heterogeneity in initial analyses. Continued analyses, combined with results of a parallel study based at UTSW (NCT06400550), will determine whether pathway‑level metabolic ratios define biologically and clinically distinct metabolic phenotypes in melanoma.