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Metabolic imaging of pancreatic ductal adenocarcinoma detects altered choline metabolism

Significance statement

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal disease that develops relatively symptom-free and is therefore advanced at the time of diagnosis. The poor prognosis of Pancreatic ductal adenocarcinoma is due to a combination of late-stage diagnosis and limited response to chemotherapy and radiotherapy that limits delivery of diagnostic imaging probes and therapeutic agents. The absence of early symptoms and effective treatments has created a critical need for identifying and developing new noninvasive biomarkers and therapeutic targets. Our results have identified aberrant choline metabolism as well as differences in lactate and glutamate in human pancreatic cancer cells and tumors in mice. These results create much-needed new possibilities to detect pancreatic cancer using 1H MRS that merit rapid investigation in human subjects. Metabolic targets in choline phospholipid metabolism and in glutaminolysis and glycolysis may provide novel treatments for a disease that has severely limited treatment options.

Metabolic Imaging of Pancreatic Ductal Adenocarcinoma Detects Altered Choline Metabolism. Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

 

Journal Reference

Penet MF1, Shah T2, Bharti S2, Krishnamachary B2, Artemov D1, Mironchik Y2, Wildes F2, Maitra A3, Bhujwalla ZM4. Clin Cancer Res. 2015 Jan 15;21(2):386-95.

1JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

2JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

3Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Departments of Pathology and Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston Texas.

4JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. [email protected]

Abstract

PURPOSE:

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal disease that develops relatively symptom-free and is therefore advanced at the time of diagnosis. The absence of early symptoms and effective treatments has created a critical need for identifying and developing new noninvasive biomarkers and therapeutic targets.

EXPERIMENTAL DESIGN:

We investigated the metabolism of a panel of Pancreatic ductal adenocarcinoma cell lines in culture and noninvasively in vivo with (1)H magnetic resonance spectroscopic  imaging (MRSI) to identify noninvasive biomarkers and uncover potential  metabolic targets.

RESULTS:

We observed elevated choline-containing compounds in the Pancreatic ductal adenocarcinoma cell lines and tumors. These elevated choline-containing compounds were easily detected by increased total choline (tCho) in vivo, in spectroscopic images obtained from tumors. Principal component analysis of the spectral data identified additional differences in metabolites between immortalized human pancreatic cells and neoplastic PDAC cells. Molecular characterization revealed overexpression of choline kinase (Chk)-α, choline transporter 1 (CHT1), and  choline  transporter-like protein 1 (CTL1) in the Pancreatic ductal adenocarcinoma cell lines and tumors.

CONCLUSIONS:

Collectively, these data identify new metabolic characteristics of Pancreatic ductal adenocarcinoma and reveal potential metabolic targets. Total choline detected with (1)H MRSI may provide an intrinsic, imaging probe-independent biomarker to complement existing techniques in detecting Pancreatic ductal adenocarcinoma. The expression of Chk-α, CHT1, and CTL1 may provide additional molecular markers in aspirated cytological samples.

©2014 American Association for Cancer Research.

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