Top

Published in:

Open Access 01-12-2019 | Positron Emission Tomography | Original research

Elimination of tumor hypoxia by eribulin demonstrated by ¹⁸F-FMISO hypoxia imaging in human tumor xenograft models

Authors: Songji Zhao, Wenwen Yu, Naoyuki Ukon, Chengbo Tan, Ken-ichi Nishijima, Yoichi Shimizu, Kei Higashikawa, Tohru Shiga, Hiroko Yamashita, Nagara Tamaki, Yuji Kuge

Published in: EJNMMI Research | Issue 1/2019

Abstract

Background

Eribulin, an inhibitor of microtubule dynamics, shows antitumor potency against a variety of solid cancers through its antivascular activity and remodeling of tumor vasculature. ¹⁸F-Fluoromisonidazole (¹⁸F-FMISO) is the most widely used PET probe for imaging tumor hypoxia. In this study, we utilized ¹⁸F-FMISO to clarify the effects of eribulin on the tumor hypoxic condition in comparison with histological findings.

Material and methods

Mice bearing a human cancer cell xenograft were intraperitoneally administered a single dose of eribulin (0.3 or 1.0 mg/kg) or saline. Three days after the treatment, mice were injected with ¹⁸F-FMISO and pimonidazole (hypoxia marker for immunohistochemistry), and intertumoral ¹⁸F-FMISO accumulation levels and histological characteristics were determined. PET/CT was performed pre- and post-treatment with eribulin (0.3 mg/kg, i.p.).

Results

The ¹⁸F-FMISO accumulation levels and percent pimonidazole-positive hypoxic area were significantly lower, whereas the number of microvessels was higher in the tumors treated with eribulin. The PET/CT confirmed that ¹⁸F-FMISO distribution in the tumor was decreased after the eribulin treatment.

Conclusions

Using ¹⁸F-FMISO, we demonstrated the elimination of the tumor hypoxic condition by eribulin treatment, concomitantly with the increase in microvessel density. These findings indicate that PET imaging using ¹⁸F-FMISO may provide the possibility to detect the early treatment response in clinical patients undergoing eribulin treatment.

Cheng J, Lei L, Xu J, Sun Y, Zhang Y, Wang X, et al. 18F-fluoromisonidazole PET/CT: a potential tool for predicting primary endocrine therapy resistance in breast cancer. J Nucl Med. 2013;54:333–40. https://doi.org/10.2967/jnumed.112.111963.CrossRefPubMed

Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, et al. Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer. 2003;97:1573–81. https://doi.org/10.1002/cncr.11246.CrossRefPubMed

Wang Z, Dabrosin C, Yin X, Fuster MM, Arreola A, Rathmell WK, et al. Broad targeting of angiogenesis for cancer prevention and therapy. Semin Cancer Biol. 2015;35 Suppl:S224–43. https://doi.org/10.1016/j.semcancer.2015.01.001.CrossRefPubMedPubMedCentral

Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, Chanthery Y, et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature. 2006;444:1083–7. https://doi.org/10.1038/nature05313.CrossRefPubMed

In GK, Hu JS, Tseng WW. Treatment of advanced, metastatic soft tissue sarcoma: latest evidence and clinical considerations. Ther Adv Med Oncol. 2017;9:533–50. https://doi.org/10.1177/1758834017712963.CrossRefPubMedPubMedCentral

Arango NP, Yuca E, Zhao M, Evans KW, Scott S, Kim C, et al. Selinexor (KPT-330) demonstrates anti-tumor efficacy in preclinical models of triple-negative breast cancer. Breast Cancer Res. 2017;19:93. https://doi.org/10.1186/s13058-017-0878-6.CrossRefPubMedPubMedCentral

Park Y, Son JY, Lee BM, Kim HS, Yoon S. Highly eribulin-resistant KBV20C oral cancer cells can be sensitized by co-treatment with the third-generation P-glycoprotein inhibitor, elacridar, at a low dose. Anticancer Res. 2017;37:4139–46.PubMed

Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther. 2005;4:1086–95. https://doi.org/10.1158/1535-7163.mct-04-0345.CrossRefPubMed

Yoshida T, Ozawa Y, Kimura T, Sato Y, Kuznetsov G, Xu S, et al. Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states. Br J Cancer. 2014;110:1497–505. https://doi.org/10.1038/bjc.2014.80.CrossRefPubMedPubMedCentral

10.

Funahashi Y, Okamoto K, Adachi Y, Semba T, Uesugi M, Ozawa Y, et al. Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Sci. 2014;105:1334–42. https://doi.org/10.1111/cas.12488.CrossRefPubMedPubMedCentral

11.

Cheal SM, Xu H, Guo HF, Patel M, Punzalan B, Fung EK, et al. Theranostic pretargeted radioimmunotherapy of internalizing solid tumor antigens in human tumor xenografts in mice: Curative treatment of HER2-positive breast carcinoma. Theranostics. 2018;8:5106–25. https://doi.org/10.7150/thno.26585.CrossRefPubMedPubMedCentral

12.

Yu W, Zhao S, Zhao Y, Fatema CN, Murakami M, Nishijima KI, et al. Changes in tumor oxygen state after sorafenib therapy evaluated by 18F-fluoromisonidazole hypoxia imaging of renal cell carcinoma xenografts. Oncol Lett. 2017;14:2341–6. https://doi.org/10.3892/ol.2017.6371.CrossRefPubMedPubMedCentral

13.

Preibisch C, Shi K, Kluge A, Lukas M, Wiestler B, Gottler J, et al. Characterizing hypoxia in human glioma: A simultaneous multimodal MRI and PET study. NMR Biomed. 2017. https://doi.org/10.1002/nbm.3775.CrossRef

14.

McGowan DR, Macpherson RE, Hackett SL, Liu D, Gleeson FV, McKenna WG, et al. 18 F-fluoromisonidazole uptake in advanced stage non-small cell lung cancer: A voxel-by-voxel PET kinetics study. Med Phys. 2017. https://doi.org/10.1002/mp.12416.CrossRef

15.

Lock S, Perrin R, Seidlitz A, Bandurska-Luque A, Zschaeck S, Zophel K, et al. Residual tumour hypoxia in head-and-neck cancer patients undergoing primary radiochemotherapy, final results of a prospective trial on repeat FMISO-PET imaging. Radiother Oncol. 2017. https://doi.org/10.1016/j.radonc.2017.08.010.CrossRef

16.

Torigian DA, Alavi A. PET Imaging of Thoracic Disease. PET clinics. 2011;6:xi. https://doi.org/10.1016/j.cpet.2011.06.001.CrossRefPubMed

17.

Masaki Y, Shimizu Y, Yoshioka T, Nishijima KI, Zhao S, Higashino K, et al. FMISO accumulation in tumor is dependent on glutathione conjugation capacity in addition to hypoxic state. Ann Nucl Med. 2017. https://doi.org/10.1007/s12149-017-1189-9.CrossRef

18.

Krohn KA, Link JM, Mason RP. Molecular imaging of hypoxia. J Nucl Med. 2008;49(Suppl 2):129s–48s. https://doi.org/10.2967/jnumed.107.045914.CrossRefPubMed

19.

Murakami M, Zhao S, Zhao Y, Chowdhury NF, Yu W, Nishijima K, et al. Evaluation of changes in the tumor microenvironment after sorafenib therapy by sequential histology and 18F-fluoromisonidazole hypoxia imaging in renal cell carcinoma. Int J Oncol. 2012;41:1593–600. https://doi.org/10.3892/ijo.2012.1624.CrossRefPubMedPubMedCentral

20.

Tang G, Wang M, Tang X, Gan M, Luo L. Fully automated one-pot synthesis of [18F]fluoromisonidazole. Nucl Med Biol. 2005;32:553–8. https://doi.org/10.1016/j.nucmedbio.2005.03.010.CrossRefPubMed

21.

Oh SJ, Chi DY, Mosdzianowski C, Kim JY, Gil HS, Kang SH, et al. Fully automated synthesis of [18F]fluoromisonidazole using a conventional [18F]FDG module. Nucl Med Biol. 2005;32:899–905. https://doi.org/10.1016/j.nucmedbio.2005.06.003.CrossRefPubMed

22.

Ukon N, Zhao S, Yu W, Shimizu Y, Nishijima KI, Kubo N, et al. Dynamic PET evaluation of elevated FLT level after sorafenib treatment in mice bearing human renal cell carcinoma xenograft. EJNMMI Res. 2016;6:90. https://doi.org/10.1186/s13550-016-0246-z.CrossRefPubMedPubMedCentral

23.

Ueda S, Saeki T, Takeuchi H, Shigekawa T, Yamane T, Kuji I, et al. In vivo imaging of eribulin-induced reoxygenation in advanced breast cancer patients: a comparison to bevacizumab. Br J Cancer. 2016;114:1212–8. https://doi.org/10.1038/bjc.2016.122.CrossRefPubMedPubMedCentral

24.

Horsman MR, Mortensen LS, Petersen JB, Busk M, Overgaard J. Imaging hypoxia to improve radiotherapy outcome. Nat Rev Clin Oncol. 2012;9:674–87. https://doi.org/10.1038/nrclinonc.2012.171.CrossRefPubMed

25.

Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev. 2007;26:225–39. https://doi.org/10.1007/s10555-007-9055-1.CrossRefPubMed

26.

Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11:393–410. https://doi.org/10.1038/nrc3064.CrossRefPubMed

27.

Mollard S, Ciccolini J, Imbs DC, El Cheikh R, Barbolosi D, Benzekry S. Model driven optimization of antiangiogenics + cytotoxics combination: application to breast cancer mice treated with bevacizumab + paclitaxel doublet leads to reduced tumor growth and fewer metastasis. Oncotarget. 2017;8(14):23087–98. https://doi.org/10.18632/oncotarget.15484.CrossRefPubMedPubMedCentral

28.

Ito K, Hamamichi S, Abe T, Akagi T, Shirota H, Kawano S, et al. Anti-tumor effects of eribulin depend on the modulation of tumor microenvironment by vascular remodeling in mouse models. Cancer Sci. 2017. https://doi.org/10.1111/cas.13392.CrossRef

29.

Towle MJ, Nomoto K, Asano M, Kishi Y, Yu MJ, Littlefield BA. Broad spectrum preclinical antitumor activity of eribulin (Halaven(R)): optimal effectiveness under intermittent dosing conditions. Anticancer Res. 2012;32:1611–9.PubMed

30.

Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA. Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase. Mol Cancer Ther. 2008;7:2003–11. https://doi.org/10.1158/1535-7163.MCT-08-0095.CrossRefPubMedPubMedCentral

31.

Terashima M, Sakai K, Togashi Y, Hayashi H, De Velasco MA, Tsurutani J, et al. Synergistic antitumor effects of S-1 with eribulin in vitro and in vivo for triple-negative breast cancer cell lines. Springerplus. 2014;3:417. https://doi.org/10.1186/2193-1801-3-417.CrossRefPubMedPubMedCentral

32.

Kitahara H, Hirai M, Kato K, Bou-Gharios G, Nakamura H, Kawashiri S. Eribulin sensitizes oral squamous cell carcinoma cells to cetuximab via induction of mesenchymal-to-epithelial transition. Oncol Rep. 2016;36:3139–44. https://doi.org/10.3892/or.2016.5189.CrossRefPubMedPubMedCentral

33.

Tsuji T, Ibaragi S, Hu GF. Epithelial-mesenchymal transition and cell cooperativity in metastasis. Cancer Res. 2009;69:7135–9. https://doi.org/10.1158/0008-5472.can-09-1618.CrossRefPubMedPubMedCentral

34.

Stathopoulos J, Armakolas A, Stathopoulos GP, Gomatos IP. Plasma VEGF levels in breast cancer patients with and without metastases. Oncol Lett. 2010;1:739–41. https://doi.org/10.3892/ol_00000129.CrossRefPubMedPubMedCentral

35.

Meng X, Vander Ark A, Lee P, Hostetter G, Bhowmick NA, Matrisian LM, et al. Myeloid-specific TGF-beta signaling in bone promotes basic-FGF and breast cancer bone metastasis. Oncogene. 2016;35:2370–8. https://doi.org/10.1038/onc.2015.297.CrossRefPubMed

36.

Dong C, Li Z, Alvarez R Jr, Feng XH, Goldschmidt-Clermont PJ. Microtubule binding to Smads may regulate TGF beta activity. Mol Cell. 2000;5:27–34.CrossRef

37.

Taylor MA, Lee YH, Schiemann WP. Role of TGF-beta and the tumor microenvironment during mammary tumorigenesis. Gene Expr. 2011;15:117–32.CrossRef

38.

Tong X, Srivatsan A, Jacobson O, Wang Y, Wang Z, Yang X, et al. Monitoring tumor hypoxia using (18)F-FMISO PET and pharmacokinetics modeling after photodynamic therapy. Sci Rep. 2016;22(6):31551. https://doi.org/10.1038/srep31551.CrossRef

39.

Asano M, Matsui J, Towle MJ, Wu J, McGonigle S, DE Boisferon MH, et al. Broad-spectrum preclinical antitumor activity of eribulin (Halaven®): combination with anticancer agents of differing mechanisms. Anticancer Res. 2018;38(6):3375–85. https://doi.org/10.21873/anticanres.12604.CrossRefPubMed

Title: Elimination of tumor hypoxia by eribulin demonstrated by 18F-FMISO hypoxia imaging in human tumor xenograft models
Authors: Songji Zhao
Wenwen Yu
Naoyuki Ukon
Chengbo Tan
Ken-ichi Nishijima
Yoichi Shimizu
Kei Higashikawa
Tohru Shiga
Hiroko Yamashita
Nagara Tamaki
Yuji Kuge
Publication date: 01-12-2019
Publisher: Springer Berlin Heidelberg
Keyword: Positron Emission Tomography
Published in: EJNMMI Research / Issue 1/2019
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/s13550-019-0521-x

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Elimination of tumor hypoxia by eribulin demonstrated by ¹⁸F-FMISO hypoxia imaging in human tumor xenograft models

Abstract

Background

Material and methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Material and methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2019

HYNIC and DOMA conjugated radiolabeled bombesin analogs as receptor-targeted probes for scintigraphic detection of breast tumor

Instant kit preparation of 68Ga-radiopharmaceuticals via the hybrid chelator DATA: clinical translation of [68Ga]Ga-DATA-TOC

Role of F-18 FDG PET/CT in non-conjunctival origin ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphomas

Pulmonary PET imaging confirms preferential lung target occupancy of an inhaled bronchodilator

Parathyroid imaging with 18F-fluorocholine PET/CT as a first-line imaging modality in primary hyperparathyroidism: a retrospective cohort study

Potential for imaging the high-affinity state of the 5-HT1B receptor: a comparison of three PET radioligands with differing intrinsic activity