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Non-Invasive Glutamine PET Reflects Pharmacological Inhibition of BRAFV600E In Vivo

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Abstract

Purpose

This study aimed to study whether cancer cells possess distinguishing metabolic features compared with surrounding normal cells, such as increased glutamine uptake. Given this, quantitative measures of glutamine uptake may reflect critical processes in oncology. Approximately, 10 % of patients with colorectal cancer (CRC) express BRAF V600E, which may be actionable with selective BRAF inhibitors or in combination with inhibitors of complementary signaling axes. Non-invasive and quantitative predictive measures of response to these targeted therapies remain poorly developed in this setting. The primary objective of this study was to explore 4-[18F]fluoroglutamine (4-[18F]F-GLN) positron emission tomography (PET) to predict response to BRAFV600E-targeted therapy in preclinical models of colon cancer.

Procedures

Tumor microarrays from patients with primary human colon cancers (n = 115) and CRC liver metastases (n = 111) were used to evaluate the prevalence of ASCT2, the primary glutamine transporter in oncology, by immunohistochemistry. Subsequently, 4-[18F]F-GLN PET was evaluated in mouse models of human BRAF V600E-expressing and BRAF wild-type CRC.

Results

Approximately 70 % of primary colon cancers and 53 % of metastases exhibited positive ASCT2 immunoreactivity, suggesting that [18F]4-F-GLN PET could be applicable to a majority of patients with colon cancer. ASCT2 expression was not associated selectively with the expression of mutant BRAF. Decreased 4-[18F]F-GLN predicted pharmacological response to single-agent BRAF and combination BRAF and PI3K/mTOR inhibition in BRAF V600E -mutant Colo-205 tumors. In contrast, a similar decrease was not observed in BRAF wild-type HCT-116 tumors, a setting where BRAFV600E-targeted therapies are ineffective.

Conclusions

4-[18F]F-GLN PET selectively reflected pharmacodynamic response to BRAF inhibition when compared with 2-deoxy-2[18F]fluoro-d-glucose PET, which was decreased non-specifically for all treated cohorts, regardless of downstream pathway inhibition. These findings illustrate the utility of non-invasive PET imaging measures of glutamine uptake to selectively predict response to BRAF-targeted therapy in colon cancer and may suggest further opportunities to inform colon cancer clinical trials using targeted therapies against MAPK activation.

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Acknowledgments

These studies were supported by grants from the National Institutes of Health (R01-CA140628, P50-CA95103, 5P30-DK058404, P30-CA068485), the Kleberg Foundation, and the Vanderbilt Center for Molecular Probes. The authors wish to thank Ping Zhao for her assistance with the animal experiments, Md. Noor Tantaway for his assistance with the small animal PET acquisition, and Michael Nickels for his assistance with radio tracer production.

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Correspondence to H. Charles Manning.

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The authors declare that they have no conflicts of interest.

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Schulte, M.L., Hight, M.R., Ayers, G.D. et al. Non-Invasive Glutamine PET Reflects Pharmacological Inhibition of BRAFV600E In Vivo . Mol Imaging Biol 19, 421–428 (2017). https://doi.org/10.1007/s11307-016-1008-z

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