A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965

Rosie Mcneillis,George Petrides,Chris Bacon,Alexandros Siskos,Hector Keun,Sarah Halford,Fiona Jenkinson,Nicola Leech,Ann Bowron,Ruth Plummer,Alastair Greystoke,Jon Walton

doi:10.1038/s41416-020-0727-8

Abstract

A 47-year-old man with metastatic melanoma presented with refractory hyperlactaemic acidosis following the first dose of the mono-carboxylase transporter 1 inhibitor AZD3965 within a “first time in man” clinical trial. The mechanism of the agent and the temporal relationship suggested that this event was potentially drug related and recruitment was suspended. However, urinary metabolomics showed extensive abnormalities even prior to drug administration, leading to investigations for an underlying metabolic disorder. The lack of clinical symptoms from the elevated lactate and low blood glucose suggested a diagnosis of “hyper-Warburgism”, where the high tumour burden was associated with extensive glucose uptake and lactate efflux from malignant cells, and the subsequent impact on blood biochemistry. This was supported by an FDG-PET scan showing extensive glucose uptake in numerous metastases and lack of uptake in the brain. A review of the literature showed 16 case reports of “hyper-Warburgism” in non-haematological malignancies, none of them with melanoma, with most associated with a poor outcome. The patient was treated symptomatically, but died 2 months later. The development of AZD3965 continues with the exclusion of patients with elevated plasma lactate at screening added to the protocol as a safety measure.Trial identification number ClinicalTrials.Gov. NCT01791595.

Highlights

We present the case of a patient with metastatic melanoma who presented with malignant lactic acidosis, this biochemical abnormality being made clinically apparent by treatment with a novel antitumour agent-targeting metabolism, AZD3965
Given the mechanism of the drug, we considered congenital monocarboxylate transporters (MCT)-4 deficiency, but strong MCT-4 expression was detected in his original tumour resection samples suggesting that this was unlikely (Supplementary Fig. 1)
Lactic acidosis is associated with high mortality,[1,8] and treatment consists of correcting the underlying cause where possible, and attempting to enhance clearance of lactate and reduce acidosis

Summary

Introduction

We present the case of a patient with metastatic melanoma who presented with malignant lactic acidosis, this biochemical abnormality being made clinically apparent by treatment with a novel antitumour agent-targeting metabolism, AZD3965.Malignant lactic acidosis is a rare complication of solid malignancies, being more common in haematological cancers. An increase in lactate production as a result of the Warburg effect in cancer cells is considered to play an important role in its pathogenesis.[1,2,3,4] The Warburg effect is considered one of the hallmarks of cancer,[5] and describes the tendency of malignant cells to favour glucose metabolism via glycolysis over oxidative phosphorylation, even in the presence of oxygen. It can potentially exploit the dependency of cancer cells on aerobic glycolysis, leading to an accumulation of intracellular lactate, feedback inhibition of glycolysis and pH imbalance

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Conclusion