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

doi:10.1007/s11307-016-1008-z

Non-Invasive Glutamine PET Reflects Pharmacological Inhibition of BRAF^V600E In Vivo

Mol Imaging Biol. 2017 Jun;19(3):421-428. doi: 10.1007/s11307-016-1008-z.

Authors

Michael L Schulte^{1

2

3}, Matthew R Hight², Gregory D Ayers⁴, Qi Liu⁵, Yu Shyr^{5

6}, M Kay Washington^{6

7}, H Charles Manning^{8

9

10

11

12

13

14

15}

Affiliations

¹ Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
² Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
³ Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
⁴ Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
⁵ Vanderbilt Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
⁶ Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
⁷ Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
⁸ Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.
⁹ Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.
¹⁰ Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.
¹¹ Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University Medical Center, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.
¹² Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.
¹³ Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.
¹⁴ Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.
¹⁵ Department of Chemistry, Vanderbilt University, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.

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 BRAF^V600E-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 BRAF^V600E-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.

Keywords: BRAF; Cancer; Colon; Glutamine; Pet.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Transport System ASC / metabolism
Animals
Cell Line, Tumor
Colonic Neoplasms / drug therapy
Colonic Neoplasms / metabolism
Colonic Neoplasms / pathology
Female
Glutamine / chemistry*
Humans
Liver Neoplasms / secondary
Mice, Nude
Minor Histocompatibility Antigens / metabolism
Mutation / genetics*
Positron-Emission Tomography*
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Proto-Oncogene Proteins B-raf / genetics*
Xenograft Model Antitumor Assays

Substances

Amino Acid Transport System ASC
Minor Histocompatibility Antigens
Protein Kinase Inhibitors
SLC1A5 protein, human
Glutamine
Proto-Oncogene Proteins B-raf

Abstract

Publication types

MeSH terms

Substances

Grants and funding