Metabolic positron emission tomography imaging of cancer: Pairing lipid metabolism with glycolysis

Abstract

The limitations of fluorine-18 fluorodeoxy-D-glucose (FDG) in detecting some cancers has prompted a longstanding search for other positron emission tomography (PET) tracers to complement the imaging of glycolysis in oncology, with much attention paid to lipogenesis based on observations that the production of various lipid and lipid-containing compounds is increased in most cancers. Radiolabeled analogs of choline and acetate have now been used as oncologic PET probes for over a decade, showing convincingly improved detection sensitivity over FDG for certain cancers. However, neither choline nor acetate have been thoroughly validated as lipogenic biomarkers, and while acetyl-CoA produced from acetate is used in de-novo lipogenesis to synthesize fatty acids, acetate is also consumed by various other synthetic and metabolic pathways, with recent experimental observations challenging the assumption that lipogenesis is its predominant role in all cancers. Since tumors detected by acetate PET are also frequently detected by choline PET, imaging of choline metabolism might serve as an alternative albeit indirect marker of lipogenesis, particularly if the fatty acids produced in cancer cells are mainly destined for membrane synthesis through incorporation into phosphatidylcholines. Aerobic glycolysis may or may not coincide with changes in lipid metabolism, resulting in combinatorial metabolic phenotypes that may have different prognostic or therapeutic implications. Consequently, PET imaging using dual metabolic tracers, in addition to being diagnostically superior to imaging with individual tracers, could eventually play a greater role in supporting precision medicine, as efforts to develop small-molecule metabolic pathway inhibitors are coming to fruition. To prepare for this advent, clinical and translational studies of metabolic PET tracers must go beyond simply estimating tracer diagnostic utility, and aim to uncover potential therapeutic avenues associated with these metabolic alterations.

Propionic Acid-Based PET Imaging of the Fatty Acid Synthesis Pathway in Prostate Cancer

“…The aim of this study was to evaluate the potential value of 2-[ 18 Grayscale scanning showed that FASN expression in the LNCaP and PC-3 tumors was 33.3% and 10.3% higher than that in the DU145 tumors, respectively. The accumulation (% ID/g) of [ 18 F]FPA in the LNCaP , PC-3 and DU145 tumors decreased by 27.6, 40.5 and 11.7%, respectively, after treatment with orlistat.…”

“…Informed consent was obtained before imaging. The patient fasted for at least 6 hours before 18 F-FDG and [ 18 F]FPA was injected intravenously. The start of PET/CT acquisition was 60 min after 18 F-FDG or [ 18 F]FPA injection (3.7 MBq/kg body weight).…”

“…The patient fasted for at least 6 hours before 18 F-FDG and [ 18 F]FPA was injected intravenously. The start of PET/CT acquisition was 60 min after 18 F-FDG or [ 18 F]FPA injection (3.7 MBq/kg body weight). Imaging was performed with a uMI 780 128-slice CT apparatus (Shanghai United Imaging Healthcare, China) in the supine position.…”

“…Fatty acids are the other principal energy source for tumor cells besides glucose and are essential constituents of membrane phospholipids and important substrates for the energy metabolism of malignant tumor cells ( Fig. 1) [17][18][19]. PCa cells are characterized by the predominant uptake of fatty acids over glucose [20,21], and lipid metabolizing enzymes are upregulated in the initial stage of PCa and throughout tumor progression [22][23][24].…”

Dysregulated metabolism: a relevant player in prostate cancer progression and clinical management

“…Increased glucose use by cancer cells is the basis for cancer detection by the uptake of the glucose analogue, fluorine-18-labeled 2-deoxy-2-fluoro-D-glucose ( 18 F-FDG) which can be visualized by positron-emission tomography (PET). PCa cells have a dominant uptake of fatty acid over glucose, alternative tracers have been proposed and PET scanning in PCa is still developing (11). Imaging with PET tracers with 11 C acetate and 11 C choline have shown sufficient sensitivity in the detection not only of primary site, but also of metastasis and recurrence (12).…”