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Multi-tracer small animal PET imaging of the tumour response to the novel pan-Erb-B inhibitor CI-1033

  • Molecular imaging
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

This study was designed as “proof of concept” for a drug development model utilising multi-tracer serial small animal PET imaging to characterise tumour responses to molecularly targeted therapy.

Methods

Mice bearing subcutaneous A431 human squamous carcinoma xenografts (n=6–8) were treated with the pan-Erb-B inhibitor CI-1033 or vehicle and imaged serially (days 0, 3 and 6 or 7) with [18F]fluorodeoxyglucose, [18F]fluoro-L-thymidine, [18F]fluoro-azoazomycinarabinoside or [18F]fluoromisonidazole. Separate cohorts (n=3) were treated identically and tumours were assessed ex vivo for markers of glucose metabolism, proliferation and hypoxia.

Results

During the study period, mean uptake of all PET tracers generally increased for control tumours compared to baseline. In contrast, tracer uptake into CI-1033-treated tumours decreased by 20–60% during treatment. Expression of the glucose transporter Glut-1 and cell cycle markers was unchanged or increased in control tumours and generally decreased with CI-1033 treatment, compared to baseline. Thymidine kinase activity was reduced in all tumours compared to baseline at day 3 but was sevenfold higher in control versus CI-1033-treated tumours by day 6 of treatment. Uptake of the hypoxia marker pimonidazole was stable in control tumours but was severely reduced following 7 days of CI-1033 treatment.

Conclusion

CI-1033 treatment significantly affects tumour metabolism, proliferation and hypoxia as determined by PET. The PET findings correlated well with ex vivo biomarkers for each of the cellular processes studied. These results confirm the utility of small animal PET for evaluation of the effectiveness of molecularly targeted therapies and simultaneously definition of specific cellular processes involved in the therapeutic response.

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References

  1. Tibes R, Trent J, Kurzrock R. Tyrosine kinase inhibitors and the dawn of molecular cancer therapeutics. Annu Rev Pharmacol Toxicol 2005;45:357–384

    Article  PubMed  CAS  Google Scholar 

  2. Sawyers C. Targeted cancer therapy. Nature 2004;432:294–297

    Article  PubMed  CAS  Google Scholar 

  3. Solomon B, McArthur G, Cullinane C, Zalcberg J, Hicks R. Applications of positron emission tomography in the development of molecular targeted cancer therapeutics. BioDrugs 2003;17:339–354

    Article  PubMed  CAS  Google Scholar 

  4. Kelloff GJ, Hoffman JM, Johnson B, Scher HI, Siegel BA, Cheng EY, et al. Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development. Clin Cancer Res 2005;11:2785–2808

    Article  PubMed  CAS  Google Scholar 

  5. Scanga DR, Martin WH, Delbeke D. Value of FDG PET imaging in the management of patients with thyroid, neuroendocrine, and neural crest tumors. Clin Nucl Med 2004;29:86–90

    Article  PubMed  Google Scholar 

  6. Avril NE, Weber WA. Monitoring response to treatment in patients utilizing PET. Radiol Clin North Am 2005;43:189–204

    Article  PubMed  Google Scholar 

  7. Lyons SK. Advances in imaging mouse tumour models in vivo. J Pathol 2005;205:194–205

    Article  PubMed  CAS  Google Scholar 

  8. Herschman HR. Micro-PET imaging and small animal models of disease. Curr Opin Immunol 2003;15:378–384

    Article  PubMed  CAS  Google Scholar 

  9. Roselt P, Meikle S, Kassiou M. The role of positron emission tomography in the discovery and development of new drugs; as studied in laboratory animals. Eur J Drug Metab Pharmacokinet 2004;29:1–6

    Article  PubMed  CAS  Google Scholar 

  10. Maschauer S, Prante O, Hoffmann M, Deichen JT, Kuwert T. Characterization of 18F-FDG uptake in human endothelial cells in vitro. J Nucl Med 2004;45:455–460

    PubMed  CAS  Google Scholar 

  11. Rajendran JG, Wilson DC, Conrad EU, Peterson LM, Bruckner JD, Rasey JS, et al. [18F]FMISO and [18F]FDG PET imaging in soft tissue sarcomas: correlation of hypoxia, metabolism and VEGF expression. Eur J Nucl Med Mol Imaging 2003;30:695–704

    Article  PubMed  CAS  Google Scholar 

  12. Plas DR, Thompson CB. Cell metabolism in the regulation of programmed cell death. Trends Endocrinol Metab 2002;13:75–78

    Article  PubMed  Google Scholar 

  13. Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 2004;64:3892–3899

    Article  PubMed  CAS  Google Scholar 

  14. Vesselle H, Grierson J, Muzi M, Pugsley JM, Schmidt RA, Rabinowitz P, et al. In vivo validation of 3'deoxy-3'-[18F]fluorothymidine ([18F]FLT) as a proliferation imaging tracer in humans: correlation of [18F]FLT uptake by positron emission tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors. Clin Cancer Res 2002;8:3315–3323

    PubMed  CAS  Google Scholar 

  15. Shields AF, Grierson JR, Dohmen BM, Machulla HJ, Stayanoff JC, Lawhorn-Crews JM, et al. Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med 1998;4:1334–1336

    Article  PubMed  CAS  Google Scholar 

  16. Piert M, Machulla H-J, Picchio M, Reischl G, Ziegler S, Kumar P, et al. Hypoxia-specific tumor imaging with 18F-fluoroazomycin arabinoside. J Nucl Med 2005;46:106–113

    PubMed  Google Scholar 

  17. Sorger D, Patt M, Kumar P, Wiebe LI, Barthel H, Seese A, et al. [18F]fluoroazomycinarabinofuranoside (18FAZA) and [18F]fluoromisonidazole (18FMISO): a comparative study of their selective uptake in hypoxic cells and PET imaging in experimental rat tumors. Nucl Med Biol 2003;30:317–326

    Article  PubMed  CAS  Google Scholar 

  18. Grierson JR, Schwartz JL, Muzi M, Jordan R, Krohn KA. Metabolism of 3'-deoxy-3'-[F-18]fluorothymidine in proliferating A549 cells: validations for positron emission tomography. Nucl Med Biol 2004;31:829–837

    Article  PubMed  CAS  Google Scholar 

  19. Barthel H, Cleij MC, Collingridge DR, Hutchinson OC, Osman S, He Q, et al. 3'-deoxy-3'-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res 2003;63:3791–3798

    PubMed  CAS  Google Scholar 

  20. Bradshaw HD Jr. Molecular cloning and cell cycle-specific regulation of a functional human thymidine kinase gene. Proc Natl Acad Sci U S A 1983;80:5588–5591

    Article  PubMed  CAS  Google Scholar 

  21. Sherley JL, Kelly TJ. Regulation of human thymidine kinase during the cell cycle. J Biol Chem 1988;263:8350–8358

    PubMed  CAS  Google Scholar 

  22. Nunn A, Linder K, Strauss HW. Nitroimidazoles and imaging hypoxia. Eur J Nucl Med 1995;22:265–280

    Article  PubMed  CAS  Google Scholar 

  23. Hockel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 2001;93:266–276

    Article  PubMed  CAS  Google Scholar 

  24. Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 2005;23:2445–2459

    Article  PubMed  CAS  Google Scholar 

  25. Abd El-Rehim DM, Pinder SE, Paish CE, Bell JA, Rampaul RS, Blamey RW et al. Expression and co-expression of the members of the epidermal growth factor receptor (EGFR) family in invasive breast carcinoma. Br J Cancer 2004;91:1532–1542

    Article  PubMed  CAS  Google Scholar 

  26. Ioachim E, Kamina S, Athanassiadou S, Agnantis NJ. The prognostic significance of epidermal growth factor receptor (EGFR), C-erbB-2, Ki-67 and PCNA expression in breast cancer. Anticancer Res 1996;16(5B):3141–3147

    PubMed  CAS  Google Scholar 

  27. Tsuda H, Morita D, Kimura M, Shinto E, Ohtsuka Y, Matsubara O et al. Correlation of KIT and EGFR overexpression with invasive ductal breast carcinoma of the solid-tubular subtype, nuclear grade 3, and mesenchymal or myoepithelial differentiation. Cancer Sci 2005;96:48–53

    Article  PubMed  CAS  Google Scholar 

  28. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5:341–354

    Article  PubMed  CAS  Google Scholar 

  29. Allen LF, Lenehan PF, Eiseman IA, Elliott WL, Fry DW. Potential benefits of the irreversible pan-erbB inhibitor, CI-1033, in the treatment of breast cancer. Semin Oncol 2002;29:11–21

    PubMed  CAS  Google Scholar 

  30. Slichenmyer WJ, Elliott WL, Fry DW. CI-1033, a pan-erbB tyrosine kinase inhibitor. Semin Oncol 2001;28:80–85

    Article  PubMed  CAS  Google Scholar 

  31. Smaill JB, Rewcastle GW, Loo JA, Greis KD, Chan OH, Reyner EL, et al. Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions. J Med Chem 2000;43:1380–1397

    Article  PubMed  CAS  Google Scholar 

  32. Erlichman C, Boerner SA, Hallgren CG, Spieker R, Wang X-Y, James CD, et al. The HER tyrosine kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10-hydroxycamptothecin and topotecan by inhibiting breast cancer resistance protein-mediated drug efflux. Cancer Res 2001;61:739–748

    PubMed  CAS  Google Scholar 

  33. Nyati MK, Maheshwari D, Hanasoge S, Sreekumar A, Rynkiewicz SD, Chinnaiyan AM, et al. Radiosensitization by pan ErbB inhibitor CI-1033 in vitro and in vivo. Clin Cancer Res 2004;10:691–700

    Article  PubMed  CAS  Google Scholar 

  34. Machulla HJ, Blocher A, Kuntzsch M, Piert M, Wei R, Grierson JR. Simplified labeling approach for synthesizing 3'-deoxy-3'-[18F]fluorothymidine ([18F]FET). J Radioanal Nucl Chem 2000;243:843–846

    Article  CAS  Google Scholar 

  35. Piert M, Machulla HJ, Kumar P, Link T, Wiebe LI. 18F labeled fluoroazamycin arabinoside (FAZA): a novel marker of tumour tissue hypoxia. J Nucl Med 2001;42:279

    Google Scholar 

  36. Surti S, Karp JS, Perkins AE, Freifelder R. TNSG. M. Design evaluation of A-PET: A high sensitivity animal PET camera. Trans Nucl Sci 2003;50:1357–1363

    Article  Google Scholar 

  37. Chiang S, Cardi C, Matej S, Zhuang H, Newberg A, Alavi A, et al. Clinical validation of fully 3-D versus 2.5-D RAMLA reconstruction on the Philips-ADAC CPET PET scanner. Nucl Med Commun 2004;25:1103–1107

    Article  PubMed  Google Scholar 

  38. Tanaka E, Kudo H. Subset-dependent relaxation in block-iterative algorithms for image reconstruction in emission tomography. Phys Med Biol 2003;48:1405–1422

    Article  PubMed  Google Scholar 

  39. Deans AJ, Simpson KJ, Trivett MK, Brown MA, McArthur GA. Brca1 inactivation induces p27(Kip1)-dependent cell cycle arrest and delayed development in the mouse mammary gland. Oncogene 2004;23:6136–6145

    Article  PubMed  CAS  Google Scholar 

  40. Stuart P, Ito M, Stewart C, Conrad SE. Induction of cellular thymidine kinase occurs at the mRNA level. Mol Cell Biol 1985;5:1490–1497

    PubMed  CAS  Google Scholar 

  41. Solomon B, Hagekyriakou J, Trivett MK, Stacker SA, McArthur GA, Cullinane C. EGFR blockade with ZD1839 ("Iressa") potentiates the antitumor effects of single and multiple fractions of ionizing radiation in human A431 squamous cell carcinoma. Epidermal growth factor receptor. Int J Radiat Oncol Biol Phys 2003;55:713–723

    Article  PubMed  CAS  Google Scholar 

  42. Sirotnak FM, Zakowski MF, Miller VA, Scher HI, Kris MG. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 2000;6:4885–4892

    PubMed  CAS  Google Scholar 

  43. Avril N. GLUT1 expression in tissue and 18F-FDG uptake. J Nucl Med 2004;45:930–932

    PubMed  CAS  Google Scholar 

  44. Mueckler M. Facilitative glucose transporters. Eur J Biochem 1994;219:713–725

    Article  PubMed  CAS  Google Scholar 

  45. Toyohara J, Waki A, Takamatsu S, Yonekura Y, Magata Y, Fujibayashi Y. Basis of FLT as a cell proliferation marker: comparative uptake studies with [3H]thymidine and [3H]arabinothymidine, and cell-analysis in 22 asynchronously growing tumor cell lines. Nucl Med Biol 2002;29:281–287

    Article  PubMed  Google Scholar 

  46. Guppy M. The hypoxic core: a possible answer to the cancer paradox. Biochem Biophys Res Commun 2002;299:676–680

    Article  PubMed  CAS  Google Scholar 

  47. Overgaard J. Clinical evaluation of nitroimidazoles as modifiers of hypoxia in solid tumors. Oncol Res 1994;6:509–518

    PubMed  CAS  Google Scholar 

  48. Anderson NG, Ahmad T, Chan K, Dobson R, Bundred NJ. ZD1839 (Iressa), a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, potently inhibits the growth of EGFR-positive cancer cell lines with or without erbB2 overexpression. Int J Cancer 2001;94:774–782

    Article  PubMed  CAS  Google Scholar 

  49. Matar P, Rojo F, Cassia R, Moreno-Bueno G, Di Cosimo S, Tabernero J, et al. Combined epidermal growth factor receptor targeting with the tyrosine kinase inhibitor gefitinib (ZD1839) and the monoclonal antibody cetuximab (IMC-C225): superiority over single-agent receptor targeting. Clin Cancer Res 2004;10:6487–6501

    Article  PubMed  CAS  Google Scholar 

  50. Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol 2005;202:654–662

    Article  PubMed  CAS  Google Scholar 

  51. Mischoulon D, Rana B, Kotliar N, Pilch PF, Bucher NL, Farmer SR. Differential regulation of glucose transporter 1 and 2 mRNA expression by epidermal growth factor and transforming growth factor-beta in rat hepatocytes. J Cell Physiol 1992;153:288–296

    Article  PubMed  CAS  Google Scholar 

  52. Bryson JM, Coy PE, Gottlob K, Hay N, Robey RB. Increased hexokinase activity, of either ectopic or endogenous origin, protects renal epithelial cells against acute oxidant-induced cell death. J Biol Chem 2002;277:11392–11400

    Article  PubMed  CAS  Google Scholar 

  53. Waldherr C, Mellinghoff IK, Tran C, Halpern BS, Rozengurt N, Safaei A, et al. Monitoring antiproliferative responses to kinase inhibitor therapy in mice with 3'-deoxy-3'-18 F-fluorothymidine PET. J Nucl Med 2005;46:114–120

    PubMed  CAS  Google Scholar 

  54. Rasey JS, Grierson JR, Wiens LW, Kolb PD, Schwartz JL. Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. J Nucl Med 2002;43:1210–1217

    PubMed  CAS  Google Scholar 

  55. Sherley JL, Kelly TJ. Regulation of human thymidine kinase during the cell cycle. J Biol Chem 1988;263:8350–8358

    PubMed  CAS  Google Scholar 

  56. Lin L, Kuroiwa N, Moriyama Y, Fujimura S. Continuous increase in phosphorylation of cytosolic thymidine kinase during proliferation of rat hepatoma JB1 cells. Oncol Rep 2003;10:665–669

    PubMed  CAS  Google Scholar 

  57. Barthel H, Cleij MC, Collingridge DR, Hutchinson OC, Osman S, He Q, et al. 3'-deoxy-3'-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res 2003;63:3791–3798

    PubMed  CAS  Google Scholar 

  58. Gerdes J, Becker MH, Key G, Cattoretti G. Immunohistological detection of tumour growth fraction (Ki-67 antigen) in formalin-fixed and routinely processed tissues. J Pathol 1992;168:85–86

    Article  PubMed  CAS  Google Scholar 

  59. Nelson JM, Fry DW. Akt, MAPK (Erk1/2), and p38 act in concert to promote apoptosis in response to ErbB receptor family inhibition. J Biol Chem 2001;276:14842–14847

    Article  PubMed  CAS  Google Scholar 

  60. Broker LE, Kruyt FA, Giaccone G. Cell death independent of caspases: a review. Clin Cancer Res 2005;11:3155–3162

    Article  PubMed  Google Scholar 

  61. Robey IF, Lien AD, Welsh SJ, Baggett BK, Gillies RJ. Hypoxia-inducible factor-1alpha and the glycolytic phenotype in tumors. Neoplasia 2005;7:324–330

    Article  PubMed  CAS  Google Scholar 

  62. Solomon B, Binns D, Roselt P, Weibe LI, McArthur GA, Cullinane C, et al. Modulation of intratumoral hypoxia by the epidermal growth factor receptor inhibitor gefitinib detected using small animal PET imaging. Mol Cancer Ther 2005;4:1417–1422

    Article  PubMed  CAS  Google Scholar 

  63. Russell KS, Stern DF, Polverini PJ, Bender JR. Neuregulin activation of ErbB receptors in vascular endothelium leads to angiogenesis. Am J Physiol 1999;277:H2205–H2211

    PubMed  CAS  Google Scholar 

  64. Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, et al. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 1997;151:1523–1530

    PubMed  CAS  Google Scholar 

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Acknowledgements

The Pre-clinical Imaging Facility was established at the Peter MacCallum Cancer Centre with a grant from the Pfizer Corporation (formerly Pharmacia) and all experimental work was supported by Pfizer Global Clinical Platforms Division. The authors acknowledge expert technical assistance provided by Ms. Susan Jackson. All experiments complied with current laws of Australia including ethics approval.

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Authors and Affiliations

  1. Centre for Molecular Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Donna S. Dorow, Peter Roselt, David Binns & Rodney J. Hicks

  2. Pharmacology and Developmental Therapeutics Laboratory, Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Carleen Cullinane

  3. Translational Research Laboratory, Trescowthick Research Laboratories, Peter MacCallum Cancer Centre,, Melbourne, Victoria, Australia

    Donna S. Dorow, Carleen Cullinane, Nelly Conus & Grant A. McArthur

  4. Melbourne University Department of Medicine, St. Vincent’s Hospital,, Melbourne, Victoria, Australia

    Grant A. McArthur & Rodney J. Hicks

  5. Global Clinical Platforms, Pfizer Global Clinical Technology, Groton, Connecticut, USA

    Timothy J. McCarthy

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  1. Donna S. Dorow
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Correspondence to Rodney J. Hicks.

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The first two authors contributed equally to the results presented in this report.

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Dorow, D.S., Cullinane, C., Conus, N. et al. Multi-tracer small animal PET imaging of the tumour response to the novel pan-Erb-B inhibitor CI-1033. Eur J Nucl Med Mol Imaging 33, 441–452 (2006). https://doi.org/10.1007/s00259-005-0039-5

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  • DOI: https://doi.org/10.1007/s00259-005-0039-5

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