Preclinical Evaluation of 4-[18F]Fluoroglutamine PET to Assess ASCT2 Expression in Lung Cancer

Abstract

Purpose Alanine-serine-cysteine transporter 2 (ASCT2) expression has been demonstrated as a promising lung cancer biomarker. (2S,4R)-4-[18F]Fluoroglutamine (4-[18F]fluoro-Gln) positron emission tomography (PET) was evaluated in preclinical models of non-small cell lung cancer as a quantitative, non-invasive measure of ASCT2 expression. Procedures In vivo microPET studies of 4-[18F]fluoro-Gln uptake were undertaken in human cell line xenograft tumor-bearing mice of varying ASCT2 levels, followed by a genetically engineered mouse model of epidermal growth factor receptor (EGFR)-mutant lung cancer. The relationship between a tracer accumulation and ASCT2 levels in tumors was evaluated by IHC and immunoblotting. Result 4-[18F]Fluoro-Gln uptake, but not 2-deoxy-2-[18F]fluoro-D-glucose, correlated with relative ASCT2 levels in xenograft tumors. In genetically engineered mice, 4-[18F]fluoro-Gln accumulation was significantly elevated in lung tumors, relative to normal lung and cardiac tissues. Conclusions 4-[18F]Fluoro-Gln PET appears to provide a non-invasive measure of ASCT2 expression. Given the potential of ASCT2 as a lung cancer biomarker, this and other tracers reflecting ASCT2 levels could emerge as precision imaging diagnostics in this setting.

Targeted Inhibition of EGFR and Glutaminase Induces Metabolic Crisis in EGFR Mutant Lung Cancer

“…Elevated protein expression of GLUT1 and SLC1A5 correlate with increased uptake of 18 F-FDG or 11 C-Gln in NSCLC, respectively (Hassanein et al, 2016; Usuda et al, 2010; Venneti et al, 2015). We show that E and E+CB treatment induced a similar decrease in GLUT1 (Figure 2E , red box ) whereas E+CB induced a more dramatic reduction in SLC1A5 and SLC38A1 (Figure 2E , blue box ).…”

“…Additionally, in vivo examination of glutamine uptake has been successfully evaluated in tumor cell lines and small animal models of cancer including NSCLC and glioma using the radiolabeled glutamine analogues L-[5-(11)C]-glutamine ( 11 C-Gln) and 4-[18F]fluoroglutamine (Hassanein et al, 2016; Qu et al, 2012; Venneti et al, 2015). Biodistribution studies in mice showed that 11 C-Gln had significant tumor uptake and retention (Qu et al, 2012).…”

Glutamine Metabolism in Cancer: Understanding the Heterogeneity

“…It is also important to note that the dispensability of glutamine in certain circumstances does not imply that anaplerosis in these cells is not required; as discussed above, cancer cells can find alternative ways to maintain an anaplerotic flux. Continued progress in targeting glutamine metabolism for cancer therapy will likely require identification of synergistic drug combinations along with careful selection of appropriate target patient groups, which could be aided by new techniques for imaging tumor glutamine metabolism in vivo [82, 85]. Collectively, recent findings on the complexities of cancer cell glutamine metabolism in vivo and ex vivo , far from ‘completing’ the field, have generated many new questions (see Outstanding Questions), and set the scene for future studies to provide novel and biologically relevant insights.…”

Metabolic Imaging of Glutamine in Cancer

“…A recent report also suggests that the uptake of 18 F-(2S,4R)4-FGln, but not 18 F-FDG, correlates with relative ASCT2 levels in xenograft tumors (15). In genetically engineered mice, 18 F-(2S,4R)4-FGln accumulation was significantly elevated in lung tumors, relative to normal lung and cardiac tissues (15). In addition, it was reported that cancers can also derive metabolic support from the surrounding stromal cells (16).…”

“…The imaging studies in this rat tumor model clearly confirmed that the agent is highly selective for tumor. A recent report also suggests that the uptake of 18 F-(2S,4R)4-FGln, but not 18 F-FDG, correlates with relative ASCT2 levels in xenograft tumors (15). In genetically engineered mice, 18 F-(2S,4R)4-FGln accumulation was significantly elevated in lung tumors, relative to normal lung and cardiac tissues (15).…”