Response to trastuzumab by HER2 expressing breast tumour xenografts is accompanied by decreased Hexokinase II, glut1 and [18F]-FDG incorporation and changes in 31P-NMR-detectable phosphomonoesters

• Published in: Cancer chemotherapy and pharmacology 2013-02, Vol.71 (2), p.473-480
• Main Authors: Smith, Tim A. D., Appleyard, M. Virginia C. L., Sharp, Sheila, Fleming, Ian N., Murray, Karen, Thompson, Alastair M.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic agents; Biological and medical sciences; Cancer Research; Cell Line, Tumor; Female; Fluorodeoxyglucose F18 - metabolism; Glucose Transporter Type 1 - analysis; Gynecology. Andrology. Obstetrics; Hexokinase - metabolism; Humans; Magnetic Resonance Spectroscopy - methods; Mammary gland diseases; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - metabolism; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, SCID; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Receptor, ErbB-2 - analysis; Trastuzumab; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-012-2032-6

Purpose Trastuzumab, effective in about 15 % of women with breast cancer, downregulates signalling through the Akt/PI3K and MAPK pathways. These pathways modulate glucose and phospholipid metabolism which can be monitored by [ 18 F]FDG-PET and 31 P-NMR spectroscopy, respectively. Here, the relationship between response of HER-2 overexpressing tumours and changes in [ 18 F]-FDG incorporation and 31 P-NMR-detectable phosphomonoesters were examined. Experimental Xenografts derived from HER2-overexpressing MDA-MB-453 human breast tumour cells were grown in SCID mice, treated with trastuzumab for 15 days, then [ 18 F]-FDG uptake determined and 31 P-NMR carried out on chemical extracts of the tumours. Western blots were carried out to determine protein expression of Hexokinase II and glut1. Results [ 18 F]-FDG incorporation, Hexokinase II and glut1 protein expression and the concentration of phosphocholine and phosphoethanolamine in chemical extracts subjected to 31 P-NMR were significantly decreased in the xenografts in the trastuzumab-treated mice compared with xenografts from the PBS-injected group. Conclusions Changes in FDG incorporation and 31 P-NMR spectral changes can accompany response of HER2-expressing breast cancer xenografts to trastuzumab. This is the first study to show parallel changes in [ 18 F]FDG- and 31 P-NMR-detectable metabolites accompany response to targeted anticancer treatment.