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European Journal of Nuclear Medicine and Molecular Imaging

Erschienen in:

12.04.2017 | Original Article

Inter-heterogeneity and intra-heterogeneity of α_vβ₃ in non-small cell lung cancer and small cell lung cancer patients as revealed by ⁶⁸Ga-RGD₂ PET imaging

verfasst von: Fei Kang, Zhe Wang, Guoquan Li, Shengjun Wang, Daliang Liu, Mingru Zhang, Mingxuan Zhao, Weidong Yang, Jing Wang

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 9/2017

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Abstract

Purpose

Integrin α_vβ₃ is the therapeutic target of the anti-angiogenic drug cilengitide. The objective of this study was to compare α_vβ₃ levels in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients, by using the positron emission tomography (PET) tracer ⁶⁸Ga-labeled dimerized-RGD (⁶⁸Ga-RGD₂).

Methods

Thirty-one patients with pathologically confirmed lung cancer were enrolled (21 were NSCLC and 10 were SCLC). PET/CT images were acquired using ⁶⁸Ga-RGD₂.¹⁸F-FDG PET/CT images were also acquired on the consecutive day as reference. The standard uptake values (SUV) and the tumor/nontarget (T/NT) values were quantitatively compared. Expression of the angiogenesis marker α_vβ₃ in NSCLC and SCLC lesions was analyzed by immunohistochemistry.

Results

The ¹⁸F-FDG SUVmax and the SUVmean were not significantly different between NSCLC and SCLC patients. The ⁶⁸Ga-RGD₂ uptake of SCLC patients was at background levels in both SUV and T/NT measurements and was significantly lower than that of NSCLC patients. The range value of ⁶⁸Ga-RGD₂ SUVmean was 4.5 in the NSCLC group and 2.2 in the SCLC group, while the variation coefficient was 36.2% and 39.3% in NSCLC and SCLC primary lesions, respectively. Heterogeneity between primary lesions and putative distant metastases was also observed in some NSCLC cases. Immunostaining showed that α_vβ₃ integrin was expressed in the cells and neovasculature of NSCLC lesions, while SCLC samples had negative expression.

Conclusions

The uptake of ⁶⁸Ga-RGD₂ in SCLC patients is significantly lower than that in NSCLC patients, indicating a lower α_vβ₃ target level for cilengitide in SCLC. Apparent intra-tumor heterogeneities of α_vβ₃ also exist in both NSCLC and SCLC. Such inter- and intra-heterogeneity of α_vβ₃ may potentially improve current applications of α_vβ₃-targeted therapy and diagnostic imaging in lung cancer.

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Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefPubMed

van Meerbeeck JP, Fennell DA, De Ruysscher DK. Small-cell lung cancer. Lancet. 2011;378:1741–55.CrossRefPubMed

Ettinger DS, Wood DE, Akerley W, Bazhenova LA, Borghaei H, Camidge DR, et al. Non-small cell lung cancer, version 6.2015. Natl Compr Canc Netw. 2015;13:515–24.CrossRef

Howlader N, Noone A, Krapcho M, Miller D, K. Bishop, Altekruse SF, et al. SEER Cancer Statistics Review, 1975–2013, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2013/, based on November 2015 SEER data submission, posted to the SEER web site, April 2016.

Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27–31.CrossRefPubMed

Boger C, Kalthoff H, Goodman SL, Behrens HM, Rocken C. Integrins and their ligands are expressed in non-small cell lung cancer but not correlated with parameters of disease progression. Virchows Arch. 2014;464:69–78.CrossRefPubMed

Liu Z, Jia B, Shi J, Jin X, Zhao H, Li F, et al. Tumor uptake of the RGD dimeric probe (99m)Tc-G3-2P4-RGD2 is correlated with integrin alphavbeta3 expressed on both tumor cells and neovasculature. Bioconjug Chem. 2010;21:548–55.CrossRefPubMed

Soldi R, Mitola S, Strasly M, Defilippi P, Tarone G, Bussolino F. Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2. EMBO J. 1999;18:882–92.CrossRefPubMedPubMedCentral

Mahabeleshwar GH, Feng W, Phillips DR, Byzova TV. Integrin signaling is critical for pathological angiogenesis. J Exp Med. 2006;203:2495–507.CrossRefPubMedPubMedCentral

10.

Robinson SD, Hodivala-Dilke KM. The role of beta3-integrins in tumor angiogenesis: context is everything. Curr Opin Cell Biol. 2011;23:630–7.CrossRefPubMed

11.

Smith JW. Cilengitide Merck. Curr Opin Investig Drugs. 2003;4:741–5.PubMed

12.

Manegold C, Vansteenkiste J, Cardenal F, Schuette W, Woll PJ, Ulsperger E, et al. Randomized phase II study of three doses of the integrin inhibitor cilengitide versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer. Investig New Drugs. 2013;31:175–82.CrossRef

13.

Vansteenkiste J, Barlesi F, Waller CF, Bennouna J, Gridelli C, Goekkurt E, et al. Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: results of an open-label, randomized, controlled phase II study (CERTO). Ann Oncol. 2015;26:1734–40.CrossRefPubMed

14.

Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–50.CrossRefPubMed

15.

Roviello G, Generali D. Is there a place for bevacizumab in patients with extensive-stage small cell lung cancer? Curr Cancer Drug Targets. 2016;16:209–14.CrossRefPubMed

16.

Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009;27:1227–34.CrossRefPubMed

17.

Lu X, Wang RF. A concise review of current radiopharmaceuticals in tumor angiogenesis imaging. Curr Pharm Des. 2012;18:1032–40.CrossRefPubMed

18.

Chen H, Niu G, Wu H, Chen X. Clinical application of radiolabeled RGD peptides for PET imaging of integrin alphavbeta3. Theranostics. 2016;6:78–92.CrossRefPubMedPubMedCentral

19.

Guo J, Guo N, Lang L, Kiesewetter DO, Xie Q, Li Q, et al. (18)F-alfatide II and (18)F-FDG dual-tracer dynamic PET for parametric, early prediction of tumor response to therapy. J Nucl Med. 2014;55:154–60.CrossRefPubMed

20.

Kang F, Wang S, Tian F, Zhao M, Zhang M, Wang Z, et al. Comparing the diagnostic potential of 68Ga-Alfatide II and 18F-FDG in differentiating between non-small cell lung cancer and tuberculosis. J Nucl Med. 2016;57:672–7.CrossRefPubMed

21.

Delbeke D, Coleman RE, Guiberteau MJ, Brown ML, Royal HD, Siegel BA, et al. Procedure guideline for tumor imaging with 18F-FDG PET/CT 1.0. J Nucl Med. 2006;47:885–95.PubMed

22.

Kang F, Ma W, Ma X, Shao Y, Yang W, Chen X, et al. Propranolol inhibits glucose metabolism and 18F-FDG uptake of breast cancer through posttranscriptional downregulation of hexokinase-2. J Nucl Med. 2014;55:439–45.CrossRefPubMedPubMedCentral

23.

Zheng K, Liang N, Zhang J, Lang L, Zhang W, Li S, et al. 68Ga-NOTA-PRGD2 PET/CT for integrin imaging in patients with lung cancer. J Nucl Med. 2015;56:1823–7.CrossRefPubMedPubMedCentral

24.

Minamimoto R, Jamali M, Barkhodari A, Mosci C, Mittra E, Shen B, et al. Biodistribution of the (1)(8)F-FPPRGD(2) PET radiopharmaceutical in cancer patients: an atlas of SUV measurements. Eur J Nucl Med Mol Imaging. 2015;42:1850–8.CrossRefPubMed

25.

Gao S, Wu H, Li W, Zhao S, Teng X, Lu H, et al. A pilot study imaging integrin alphavbeta3 with RGD PET/CT in suspected lung cancer patients. Eur J Nucl Med Mol Imaging. 2015;42:2029–37.CrossRefPubMed

26.

Iagaru A, Mosci C, Mittra E, Zaharchuk G, Fischbein N, Harsh G, et al. Glioblastoma Multiforme recurrence: an exploratory study of (18)F FPPRGD2 PET/CT. Radiology. 2015;277:497–506.CrossRefPubMed

27.

Reardon DA, Fink KL, Mikkelsen T, Cloughesy TF, O’Neill A, Plotkin S, et al. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol. 2008;26:5610–7.CrossRefPubMed

28.

Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1100–8.CrossRefPubMed

29.

Chinot OL. Cilengitide in glioblastoma: when did it fail? Lancet Oncol. 2014;15:1044–5.CrossRefPubMed

30.

Reynolds AR, Hart IR, Watson AR, Welti JC, Silva RG, Robinson SD, et al. Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat Med. 2009;15:392–400.CrossRefPubMed

31.

Minamimoto R, Karam A, Jamali M, Barkhodari A, Gambhir SS, Dorigo O, et al. Pilot prospective evaluation of (18)F-FPPRGD2 PET/CT in patients with cervical and ovarian cancer. Eur J Nucl Med Mol Imaging. 2016;43:1047–55.CrossRefPubMed

32.

Iagaru A, Mosci C, Shen B, Chin FT, Mittra E, Telli ML, et al. (18)F-FPPRGD2 PET/CT: pilot phase evaluation of breast cancer patients. Radiology. 2014;273:549–59.CrossRefPubMed

33.

Haubner R, Weber WA, Beer AJ, Vabuliene E, Reim D, Sarbia M, et al. Noninvasive visualization of the activated alphavbeta3 integrin in cancer patients by positron emission tomography and [18F]Galacto-RGD. PLoS Med. 2005;2:e70.CrossRefPubMedPubMedCentral

34.

Kenny LM, Coombes RC, Oulie I, Contractor KB, Miller M, Spinks TJ, et al. Phase I trial of the positron-emitting Arg-Gly-asp (RGD) peptide radioligand 18F-AH111585 in breast cancer patients. J Nucl Med. 2008;49:879–86.CrossRefPubMed

35.

Bach-Gansmo T, Danielsson R, Saracco A, Wilczek B, Bogsrud TV, Fangberget A, et al. Integrin receptor imaging of breast cancer: a proof-of-concept study to evaluate 99mTc-NC100692. J Nucl Med. 2006;47:1434–9.PubMed

36.

Zhu Z, Miao W, Li Q, Dai H, Ma Q, Wang F, et al. 99mTc-3PRGD2 for integrin receptor imaging of lung cancer: a multicenter study. J Nucl Med. 2012;53:716–22.CrossRefPubMed

37.

Kim JH, Lee JS, Kang KW, Lee H-Y, Han S-W, Kim T-Y, et al. Whole-body distribution and radiation dosimetry of 68Ga-NOTA-RGD, a positron emission tomography agent for angiogenesis imaging. Cancer Biother Radiophar. 2012;27:65–71.CrossRef

38.

Mittra ES, Goris ML, Iagaru AH, Kardan A, Burton L, Berganos R, et al. Pilot pharmacokinetic and dosimetric studies of 18F-FPPRGD2: a PET radiopharmaceutical agent for imaging αvβ3 integrin levels. Radiology. 2011;260:182–91.CrossRefPubMedPubMedCentral

Titel: Inter-heterogeneity and intra-heterogeneity of αvβ3 in non-small cell lung cancer and small cell lung cancer patients as revealed by 68Ga-RGD2 PET imaging
verfasst von: Fei Kang
Zhe Wang
Guoquan Li
Shengjun Wang
Daliang Liu
Mingru Zhang
Mingxuan Zhao
Weidong Yang
Jing Wang
Publikationsdatum: 12.04.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 9/2017
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-017-3696-2

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

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