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

Michael L. Schulte, Matthew R. Hight, Gregory D. Ayers, Qi Liu, Yu Shyr, M. Kay Washington, H. Charles Manning

研究成果: Article同行評審

12 引文 斯高帕斯(Scopus)

摘要

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 BRAFV600E, 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 BRAFV600E-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 BRAFV600E-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.

原文English
頁(從 - 到)421-428
頁數8
期刊Molecular Imaging and Biology
19
發行號3
DOIs
出版狀態Published - 2017 6月 1

All Science Journal Classification (ASJC) codes

  • 腫瘤科
  • 放射學、核子醫學和影像學
  • 癌症研究

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