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 phosphomonesters

Tim A. D. Smith*, M. Virginia C. L. Appleyard, Sheila Sharp, Ian N. Fleming, Karen Murray, Alastair M. Thompson

*Corresponding author for this work

Research output: Contribution to journal › Article

15 Citations (Scopus)

Abstract

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 [18F]FDG-PET and 31P-NMR spectroscopy respectively. Here the relationship between response of HER-2 overexpressing tumours and changes in [18F]-FDG incorporation and 31P-NMR detectable phosphomonesters 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 [18F]-FDG uptake determined and 31P-NMR carried out on chemical extracts of the tumours. Western blots were carried out to determine protein expression of Hexokinase 2 and glut1. Results: [18F]-FDG incorporation, hexokinase II and glut1 protein expression and the concentration of phosphocholine and phosphoethanolamine in chemical extracts subjected to 31P-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 31P-NMR spectral changes can accompany response of HER2 expressing breast cancer xenografts to trastuzumab. This is the first study to show parallel changes in [18F]FDG and 31P-NMR detectable metabolites accompany response to targeted anti-cancer treatment.
Original languageEnglish
Pages (from-to)473-480
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume71
Issue number2
Early online date24 Nov 2012
DOIs
Publication statusPublished - Feb 2013

Keywords

  • [18F]FDG
  • 31P-NMR
  • trastuzumab
  • hexokinase
  • xenograft

Cite this

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 phosphomonesters. / Smith, Tim A. D.; Appleyard, M. Virginia C. L.; Sharp, Sheila; Fleming, Ian N.; Murray, Karen; Thompson, Alastair M.

In: Cancer Chemotherapy and Pharmacology, Vol. 71, No. 2, 02.2013, p. 473-480.

Research output: Contribution to journal › Article

Smith, TAD, Appleyard, MVCL, Sharp, S, Fleming, IN, Murray, K & Thompson, AM 2013, '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 phosphomonesters', Cancer Chemotherapy and Pharmacology, vol. 71, no. 2, pp. 473-480. https://doi.org/10.1007/s00280-012-2032-6
Smith TAD, Appleyard MVCL, Sharp S, Fleming IN, Murray K, Thompson AM. 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 phosphomonesters. Cancer Chemotherapy and Pharmacology. 2013 Feb;71(2):473-480. https://doi.org/10.1007/s00280-012-2032-6
Smith, Tim A. D. ; Appleyard, M. Virginia C. L. ; Sharp, Sheila ; Fleming, Ian N. ; Murray, Karen ; Thompson, Alastair M. / 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 phosphomonesters. In: Cancer Chemotherapy and Pharmacology. 2013 ; Vol. 71, No. 2. pp. 473-480.
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title = "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 phosphomonesters",
abstract = "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 [18F]FDG-PET and 31P-NMR spectroscopy respectively. Here the relationship between response of HER-2 overexpressing tumours and changes in [18F]-FDG incorporation and 31P-NMR detectable phosphomonesters 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 [18F]-FDG uptake determined and 31P-NMR carried out on chemical extracts of the tumours. Western blots were carried out to determine protein expression of Hexokinase 2 and glut1. Results: [18F]-FDG incorporation, hexokinase II and glut1 protein expression and the concentration of phosphocholine and phosphoethanolamine in chemical extracts subjected to 31P-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 31P-NMR spectral changes can accompany response of HER2 expressing breast cancer xenografts to trastuzumab. This is the first study to show parallel changes in [18F]FDG and 31P-NMR detectable metabolites accompany response to targeted anti-cancer treatment.",
keywords = "[18F]FDG, 31P-NMR, trastuzumab, hexokinase, xenograft",
author = "Smith, {Tim A. D.} and Appleyard, {M. Virginia C. L.} and Sheila Sharp and Fleming, {Ian N.} and Karen Murray and Thompson, {Alastair M.}",
note = "This work was funded by the BBSRC and Breast Cancer research Campaign. NMR spectroscopy was carried out by Mr Russell Gray of the School of Natural Sciences and Computing at Aberdeen University.",
year = "2013",
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doi = "10.1007/s00280-012-2032-6",
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T1 - 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 phosphomonesters

AU - Smith, Tim A. D.

AU - Appleyard, M. Virginia C. L.

AU - Sharp, Sheila

AU - Fleming, Ian N.

AU - Murray, Karen

AU - Thompson, Alastair M.

N1 - This work was funded by the BBSRC and Breast Cancer research Campaign. NMR spectroscopy was carried out by Mr Russell Gray of the School of Natural Sciences and Computing at Aberdeen University.

PY - 2013/2

Y1 - 2013/2

N2 - 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 [18F]FDG-PET and 31P-NMR spectroscopy respectively. Here the relationship between response of HER-2 overexpressing tumours and changes in [18F]-FDG incorporation and 31P-NMR detectable phosphomonesters 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 [18F]-FDG uptake determined and 31P-NMR carried out on chemical extracts of the tumours. Western blots were carried out to determine protein expression of Hexokinase 2 and glut1. Results: [18F]-FDG incorporation, hexokinase II and glut1 protein expression and the concentration of phosphocholine and phosphoethanolamine in chemical extracts subjected to 31P-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 31P-NMR spectral changes can accompany response of HER2 expressing breast cancer xenografts to trastuzumab. This is the first study to show parallel changes in [18F]FDG and 31P-NMR detectable metabolites accompany response to targeted anti-cancer treatment.

AB - 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 [18F]FDG-PET and 31P-NMR spectroscopy respectively. Here the relationship between response of HER-2 overexpressing tumours and changes in [18F]-FDG incorporation and 31P-NMR detectable phosphomonesters 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 [18F]-FDG uptake determined and 31P-NMR carried out on chemical extracts of the tumours. Western blots were carried out to determine protein expression of Hexokinase 2 and glut1. Results: [18F]-FDG incorporation, hexokinase II and glut1 protein expression and the concentration of phosphocholine and phosphoethanolamine in chemical extracts subjected to 31P-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 31P-NMR spectral changes can accompany response of HER2 expressing breast cancer xenografts to trastuzumab. This is the first study to show parallel changes in [18F]FDG and 31P-NMR detectable metabolites accompany response to targeted anti-cancer treatment.

KW - [18F]FDG

KW - 31P-NMR

KW - trastuzumab

KW - hexokinase

KW - xenograft

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DO - 10.1007/s00280-012-2032-6

M3 - Article

VL - 71

SP - 473

EP - 480

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 2

ER -

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