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 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 [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 II 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 anticancer treatment.
Similar content being viewed by others
References
Rousseau C, Devillers A, Sagan C, Ferrer L, Bridji B, Campion L et al (2006) Monitoring of early response to neoadjuvant chemotherapy in stage II and III breast cancer by [F-18]fluorodeoxyglucose positron emission tomography. J Clin Oncol 24:5366–5372
Berriolo-Riedinger A, Touzery C, Riedinger JM, Toubeau M, Coudert B, Arnould L et al (2007) [F-18]FDG-PET predicts complete pathological response of breast cancer to neoadjuvant chemotherapy. Eur J Nucl Med Mol Imag 34:1915–1924
Dunnwald LK, Gralow JR, Ellis GK, Livingston RB, Linden HM, Specht JM et al (2008) Tumor metabolism and blood flow changes by positron emission tomography: relation to survival in patients treated with neoadjuvant chemotherapy for locally advanced breast cancer. J Clin Oncol 26:4449–4457
Specht JM, Tam SL, Kurland BF, Gralow JR, Livingston RB, Linden HM et al (2007) Serial 2-[F-18] fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) to monitor treatment of bone-dominant metastatic breast cancer predicts time to progression (TTP). Breast Cancer Res Treat 105:87–94
Jerome L, Alami N, Belanger S, Page V, Yu QN, Paterson J et al (2006) Recombinant human insulin-like growth factor binding protein 3 inhibits growth of human epidermal growth factor receptor-2-overexpressing breast tumors and potentiates Herceptin activity in vivo. Cancer Res 66:7245–7252
Paik JY, Ko BH, Jung KH, Lee KH (2009) Fibronectin Stimulates Endothelial Cell F-18-FDG Uptake Through Focal Adhesion Kinase-Mediated Phosphatidylinositol 3-Kinase/Akt Signaling. J Nucl Med 50:618–624
Kelly C, Smallbone K, Brady M (2008) Tumour glycolysis: the many faces of HIF. J Theoret Biol 254:508–513
Kawada K, Murakami K, Sato T, Kojima Y, Ebi H, Mukai H, Tahara M, Shimokata K, Minami H (2007) Prospective study of positron emission tomography for evaluation of the activity of lapatinib, a dual inhibitor of the ErbB1 and ErbB2 tyrosine kinases, in patients with advanced tumors. Jpn J Clin Oncol 37:44–48
McLarty K, Fasih A, Scollard DA, Done SJ, Vines DC, Green DE et al (2009) F-18-FDG small-animal PET/CT differentiates trastuzumab-responsive from unresponsive human breast cancer xenografts in athymic mice. J Nucl Med 50:1848–1856
Shah C, Miller TW, Wyatt SK, McKinley ET, Olivares MG, Sanchez V et al (2009) Imaging biomarkers predict response to Anti-HER2 (ErbB2) therapy in preclinical models of breast cancer. Clin Cancer Res 15:4712–4721
Griffiths JR, Tate AR, Howe FA, Stubbs M (2002) Magnetic resonance spectroscopy of cancer—practicalities of multi-centre trials and early results in non-Hodgkin’s lymphoma. Eur J Cancer 38:2085–2093
Leach MO, Verrill M, Glaholm J, Smith TAD, Collins DJ, Payne GS, Sharp JC, Ronen SM, McCready VR, Powles TJ, Smith IE (1998) Measurements of human breast cancer using magnetic resonance spectroscopy: a review of clinical measurements and a report of localized P-31 measurements of response to treatment. NMR Biomed 11:314–340
Mansi L, Ciarmiello A, Cuccurullo V (2012) PET/MRI and the revolution of the third eye. Eur J Nucl Med Mol Imag 39:1519–1524
Plosker G, Keam S (2006) Trastuzumab: a review of its use in the management of HER2-positive metastatic and early-stage breast cancer. Drugs 66:449–475
Fueger BJ, Czernin J, Hildebrandt I, Tran C, Halpern BS, Stout D, Phelps ME, Weber WA (2006) Impact of animal handling on the results of 18F-FDG PET studies in mice. J Nucl Med 47:999–1006
Purdie CA, Jordan LB, McCullough JB, Edwards SL, Cunningham J, Walsh M et al (2010) HER2 assessment on core biopsy specimens using monoclonal antibody CB11 accurately determines HER2 status in breast carcinoma. Histopathology 56:702–707
Zhang D, Salto-Tellez M, Do E, Putti TC, Koay ESC (2003) Evaluation of HER-2/neu oncogene status in breast tumors on tissue microarrays. Hum Pathol 34:362–368
Aitken SJ, Thomas JS, Langdon SP, Harrison DJ, Faratian D (2010) Quantitative analysis of changes in ER, PR and HER2 expression in primary breast cancer and paired nodal metastases. Ann Oncol 21:1254–1261
Thompson AM, Jordan LB, Quinlan P, Skene A, Dewar JA, Purdie CA (2010). Prospective comparison of switches in biomarker status between primary and recurrent breast cancer: the Breast Recurrence In: Tissues Study (BRITS). Breast Cancer Res. 12 Article Number: R92
Faratian D, Goltsov A, Lebedeva G, Sorokin A, Moodie S, Mullen P et al (2009) Systems biology reveals new strategies for personalising cancer medicine and confirms the role of PTEN in resistance to trastuzumab. Cancer Res 69:6713–6720
Al-Saffar NMS, Jackson LE, Raynaud FI, Clarke PA, de Molina AR, Lacal JC et al (2010) The phosphoinositide 3-Kinase inhibitor PI-103 downregulates choline kinase a leading to phosphocholine and total choline decrease detected by magnetic resonance spectroscopy. Cancer Res 70:5507–5517
Leach MO (2006) Magnetic resonance spectroscopy (MRS) in the investigation of cancer at The Royal Marsden Hospital and The Institute of Cancer Research. Phys Med Biol 51:R61–R82
Smith TAD, Glaholm J, Leach MO, Machin L, McCready VR (1991) The effect of intra-tumor heterogeneity on the distribution of phosphorus-containing metabolites within human breast-tumors—an invitro study using p-31 nmr-spectroscopy. NMR Biomed 4:262–267
Morse DL, Raghunand N, Sadarangani P, Murthi S, Job C, Day S, Howison C, Gillies RJ (2007) Response of choline metabolites to docetaxel therapy is quantified in vivo by localized P-31 MRS of human breast cancer xenografts and in vitro by high-resolution P-31 NMR spectroscopy of cell extracts. Magn Reson Med 58:270–280
Beloueche-Babari M, Jackson LE, Al-Saffar NMS, Workman P, Leach MO, Ronen SM (2005) Magnetic resonance spectroscopy monitoring of mitogen-activated protein kinase signalling inhibition. Cancer Res 65:3356–3363
Jordan NF, Black K, Robey IF, Runquist M, Powis G, Gillies RJ (2005) Metabolite changes in HT-29 xenograft tumors following HIF-1 alpha inhibition with PX-478 as studied by MR spectroscopy in vivo and ex vivo. NMR Biomed 18:430–439
Griffiths JR, Tate AR, Howe FA, Stubbs M (2002) Magnetic resonance spectroscopy of cancer—practicalities of multi-centre trials and early results in non-Hodgkin’s lymphoma. Eur J Cancer 38:2085–2093
Wijnen JP, van der Kemp WJM, Luttje MP, Korteweg MA, Luijten PR, Klomp DWJ (2012) Quantitative 31P magnetic resonance spectroscopy of the human breast at 7 T. Mag Resonan Med 68:339–348
Langer A (2010). A systematic review of PET and PET/CT in oncology: a way to personalize cancer treatment in a cost-effective manner? BMC Health Services Res. 10 Article Number: 283
Takahashi R, Hirata H, Tachibana I, Shimosegawa E, Inoue A, Nagatomo I, Takeda Y, Kida H, Goya S, Kijima T, Yoshida M, Kumagai T, Kumanogoh A, Okumura M, Hatazawa J, Kawase I (2012) Early [F-18]Fluorodeoxyglucose positron emission tomography at two days of gefitinib treatment predicts clinical outcome in patients with adenocarcinoma of the lung. Clin Cancer Res 18:220–228
Mileshkin L, Hicks RJ, Hughes BGM, Mitchell PLR, Charu V, Gitlitz BJ, Macfarlane D, Solomon B, Amler LC, Yu W, Pirzkall A, Fine BM (2011) Changes in F-18-Fluorodeoxyglucose and F-18-Fluorodeoxythymidine positron emission tomography imaging in patients with non-small cell lung cancer treated with erlotinib. Clin Cancer Res 17:3304–3315
Smith TAD (2001)The rate-limiting step for tumor [F-18]fluoro-2-deoxy-D-glucose (FDG) incorporation. Nucl Med Biol 28:1–4
Cheyne RW, Trembleau L, McLaughlin AC, Smith TAD (2011) Changes in 2-Fluoro-2-deoxy-d-glucose incorporation, hexokinase activity and lactate production by breast cancer cells responding to treatment with the anti-HER-2 antibody trastuzumab. Nucl Med Biol 38:339–346
Hasui M, Saikawa Y, Miura M et al (1989) Effector and precursor phenotypes of lymphokine-activated killer cells in mice with severe combined immunodeficiency (SCID) and athymic (nude) mice. Cell Immunol 120:230–239
Barok M, Isola J, Palyi-Krekk Z, Nagy P, Juhasz I, Vereb G et al (2007) Trastuzumab causes antibody-dependent cellular cytotoxicity-mediated growth inhibition of sub macroscopic JIMT-1 breast cancer xenografts despite intrinsic drug resistance. Mol Cancer Therapeut 6:2065–2072
Leyland-Jones B, Gelmon K, Ayoub JP, Arnold A, Verma S, Dias R, Ghahramani P (2003) Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin Oncol 21:3965–3971
Zhang NY, Liu LM, Dumitru DT et al (2011) Glycoengineered Pichia produced anti-HER2 is comparable to trastuzumab in preclinical study. MABS 3:289–298
Acknowledgments
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.
Conflict of interest
The authors declare they have no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Smith, T.A.D., Appleyard, M.V.C.L., Sharp, S. et al. 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. Cancer Chemother Pharmacol 71, 473–480 (2013). https://doi.org/10.1007/s00280-012-2032-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-012-2032-6