Abstract
Cancers develop metabolic strategies to cope with their microenvironment often characterized by hypoxia, limited nutrient bioavailability and exposure to anticancer treatments. Among these strategies, the metabolic symbiosis based on the exchange of lactate between hypoxic/glycolytic cancer cells that convert glucose to lactate and oxidative cancer cells that preferentially use lactate as an oxidative fuel optimizes the bioavailability of glucose to hypoxic cancer cells. This metabolic cooperation has been described in various human cancers and can provide resistance to anti-angiogenic therapies. It depends on the expression and activity of monocarboxylate transporters (MCTs) at the cell membrane. MCT4 is the main facilitator of lactate export by glycolytic cancer cells, and MCT1 is adapted for lactate uptake by oxidative cancer cells. While MCT1 inhibitor AZD3965 is currently tested in phase I clinical trials and other inhibitors of lactate metabolism have been developed for anticancer therapy, predicting and monitoring a response to the inhibition of lactate uptake is still an unmet clinical need. Here, we report the synthesis, evaluation and in vivo validation of (±)-[18F]-3-fluoro-2-hydroxypropionate ([18F]-FLac) as a tracer of lactate for positron emission tomography. [18F]-FLac offers the possibility to monitor MCT1-dependent lactate uptake and inhibition in tumors in vivo.
Highlights
Metabolic plasticity is a hallmark of cancer cells allowing them to optimally use existing resources for energy production and biosynthesis
While MCT1 inhibitor AZD3965 is currently tested in phase I clinical trials and other inhibitors of lactate metabolism have been developed for anticancer therapy, predicting and monitoring a response to the inhibition of lactate uptake is still an unmet clinical need
We report the original synthesis and preclinical validation of (±)-[18F]-3-fluoro-2-hydroxypropionate ([18F]FLac) as a tracer of lactate uptake for positron emission tomography (PET). [18F]-FLac was generated in clinical settings and evaluated in the same cancer model that served for the discovery of the metabolic symbiosis of cancers
Summary
Metabolic plasticity is a hallmark of cancer cells allowing them to optimally use existing resources for energy production and biosynthesis. MCT4/SLC16A3, which has the lowest affinity for lactate (Km 22-28 mM) but a high turnover rate, is well adapted to facilitate the export of lactate and protons by glycolytic cancer cells [8,9,10]. This isoform is hypoxiainducible (SLC16A3 is a direct target gene of hypoxiainducible factor-1 [HIF-1]) [11] and does not efficiently transport pyruvate (Km 153 mM) [4, 8, 12]. Compared to MCT1 and MCT4, MCT2/SLC16A7 and MCT3/SLC16A8 are less often expressed in cancers [4]
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