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Therapeutic efficacy and imaging assessment of the HER2-targeting chemotherapy drug ZHER2:V2-pemetrexed in lung adenocarcinoma Xenografts

  • Jingya Han
  • Yan Zhao
  • Xinming ZhaoEmail author
  • Tuo Ma
  • Tiancheng Hao
  • Jiahui Liu
  • Zhaoqi Zhang
  • Jingmian Zhang
  • Jianfang Wang
PRECLINICAL STUDIES
  • 52 Downloads

Summary

Chemotherapy has always been the first therapeutic option for patients with advanced non-small cell lung cancer (NSCLC) with untreatable oncogenic mutations. However, chemotherapy has demonstrated limited success and is associated with severe side effects. This research aimed to investigate the antitumor efficacy and cytotoxic safety of the conjugate ZHER2:V2-pemetrexed, a novel targeted chemotherapeutic drug. In this context, human epidermal growth factor receptor 2 (HER2) + A549 lung xenografts were treated using ZHER2:V2-pemetrexed, pemetrexed or physiological saline. Therapeutic efficacy was monitored by single photon emission computed tomography (SPECT) imaging using the 99mTc-labeled ZHER2:V2-pemetrexed conjugate and further confirmed by performing apoptosis assays using flow cytometry analysis and hematoxylin-eosin (H&E) staining. To evaluate the expression of HER2 in tumor tissues, immunohistochemistry was performed, accompanied by quantitative analysis using flow cytometry. A toxicological evaluation was also conducted. Imaging with 99mTc-ZHER2:V2-pemetrexed demonstrated that in HER2+ A549 models, ZHER2:V2-pemetrexed showed better antineoplastic effects than pemetrexed. Compared with pemetrexed, the results from the pathological and flow cytometry analyses also revealed that ZHER2:V2-pemetrexed exhibits high antitumor activity against A549 tumors, inducing necrosis, apoptosis and cell cycle arrest. In addition, the clinical signs of toxicity in the ZHER2:V2-pemetrexed treated group were reduced compared with those in the pemetrexed treated group. These data revealed that the ZHER2:V2-pemetrexed conjugate encompasses promising targeted antitumor activity against HER2-positive lung adenocarcinoma, with reduced side effects compared with pemetrexed. Thus, the ZHER2:V2-pemetrexed conjugate may serve as a novel molecular agent with tremendous clinical breakthrough potential in the diagnosis and treatment of HER2-positive lung adenocarcinoma.

Keywords

HER2 Affibody 99mTc-ZHER2:V2-pemetrexed Molecular imaging Pemetrexed Therapeutic response 

Notes

Acknowledgments

This study was supported by funds from the National Natural Science Foundation of China (NSFC) project (NO. 81571702). The authors would like to acknowledge the assistance of all coworkers involved in the study.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analyses were performed by Jingya Han, Tiancheng Hao, Tuo Ma and Jiahui Liu. The first draft of the manuscript was written by Jingya Han. The manuscript was reviewed by Xinming Zhao and Yan Zhao. All authors commented on previous versions of the manuscript. All authors have read and approved the final manuscript.

Funding

This study was supported by funds from the National Natural Science Foundation of China (NSFC) project (NO. 81571702).

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in this study involving animals were in accordance with the ethical standards of the Laboratory Animal Ethical Committee of the Fourth Hospital Hebei Medical University (SCXK[JI] 2013–0051).

Informed consent

For this type of study, formal consent is not required.

References

  1. 1.
    Hu J, Qia GS, Bai CX, Lung Cancer Study Group of Chinese Thoracic Society and Chinese Alliance Against Lung Cancer Expert Grouper (2015) Chinese consensus on early diagnosis of primary lung cancer (2014 version). Cancer 121(17):3157–3164CrossRefGoogle Scholar
  2. 2.
    Yoshizawa A, Sumiyoshi S, Sonobe M, Kobayashi M, Uehara T, Fujimoto M, Tsuruyama T, Date H, Haga H (2014) HER2 status in lung adenocarcinoma: a comparison of immunohistochemistry, fluorescence in situ hybridization (FISH), dual-ISH, and gene mutations. Lung Cancer 85(3):373–378CrossRefGoogle Scholar
  3. 3.
    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424CrossRefGoogle Scholar
  4. 4.
    Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA (2008) Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 83(5):584–594CrossRefGoogle Scholar
  5. 5.
    Zhang Z, Zhao X, Ding C, Wang J, Zhang J, Wang F (2016) (99m)Tc-3PRGD2 SPECT/CT imaging for monitoring early response of EGFR-TKIs therapy in patient with advanced-stage lung adenocarcinoma. Cancer Biother Radiopharm 31(7):238–245CrossRefGoogle Scholar
  6. 6.
    Jamal-Hanjani M, Wilson GA, McGranahan N et al (2017) Tracking the evolution of non-small-cell lung Cancer. N Engl J Med 376(22):2109–2121CrossRefGoogle Scholar
  7. 7.
    Li M, Zhang Q, Fu P, Li P, Peng A, Zhang G, Song X, Tan M, Li X, Liu Y, Wu Y, Fan S, Wang C (2012) Pemetrexed plus platinum as the first-line treatment option for advanced non-small cell lung cancer: a meta-analysis of randomized controlled trials. PLoS One 7(5):e37229CrossRefGoogle Scholar
  8. 8.
    Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26(21):3543–3551CrossRefGoogle Scholar
  9. 9.
    Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, Mok TS, Reck M, Van Schil PE, Hellmann MD, Peters S (2019) Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 30(5):863–870CrossRefGoogle Scholar
  10. 10.
    Olver I, Carey M, Boyes A, Hall A, Noble N, Bryant J, Walsh J, Sanson-Fisher R (2018) The timeliness of patients reporting the side effects of chemotherapy. Support Care Cancer 26(10):3579–3586CrossRefGoogle Scholar
  11. 11.
    Barnes KR, Kutikov A, Lippard SJ (2004) Synthesis, characterization, and cytotoxicity of a series of estrogen-tethered platinum (IV) complexes. Chem Biol 11(4):557–564CrossRefGoogle Scholar
  12. 12.
    Mukhopadhyay S, Barnés CM, Haskel A, Short SM, Barnes KR, Lippard SJ (2008) Conjugated platinum (IV)-peptide complexes for targeting angiogenic tumor vasculature. Bioconjug Chem 19(1):39–49CrossRefGoogle Scholar
  13. 13.
    Flygare JA, Pillow TH, Aristoff P (2013) Antibody-drug conjugates for the treatment of cancer. Chem Biol Drug Des 81(1):113–121CrossRefGoogle Scholar
  14. 14.
    Stack GD, Walsh JJ (2012) Optimising the delivery of tubulin targeting agents through antibody conjugation. Pharm Res 29(11):2972–2984CrossRefGoogle Scholar
  15. 15.
    Pallis AG, Syrigos KN (2013) Lung cancer in never smokers: disease characteristics and risk factors. Crit Rev Oncol Hematol 88(3):494–503CrossRefGoogle Scholar
  16. 16.
    Altai M, Varasteh Z, Andersson K, Eek A, Boerman O, Orlova A (2013) In vivo and in vitro studies on renal uptake of radiolabeled affibody molecules for imaging of HER2 expression in tumors. Cancer Biother Radiopharm 28(3):187–195CrossRefGoogle Scholar
  17. 17.
    Hong Z, Mao X, You J, Liu Z, Shi Y (2018) An evaluation of HER2-positive ovarian carcinoma Xenografts: from a novel therapy to a noninvasive monitoring method. Cancer Biother Radiopharm 33(9):411–419CrossRefGoogle Scholar
  18. 18.
    Alavizadeh SH, Akhtari J, Badiee A, Golmohammadzadeh S, Jaafari MR (2016) Improved therapeutic activity of HER2 Affibody-targeted cisplatin liposomes in HER2-expressing breast tumor models. Expert Opin Drug Deliv 13(3):325–336CrossRefGoogle Scholar
  19. 19.
    Curea FG, Hebbar M, Ilie SM, Bacinschi XE, Trifanescu OG, Botnariuc I, Anghel RM (2017) Current targeted therapies in HER2-positive gastric adenocarcinoma. Cancer Biother Radiopharm 32(10):351–363CrossRefGoogle Scholar
  20. 20.
    Cui N, Shi J, Yang C (2018) HER2-Based Immunotherapy for breast cancer. Cancer Biother Radiopharm 33(5):169–175CrossRefGoogle Scholar
  21. 21.
    Massicano AVF, Lee S, Crenshaw BK, Aweda TA, El Sayed R, Super I, Bose R, Marquez-Nostra BV, Lapi SE (2019) Imaging of HER2 with [89Zr]pertuzumab in response to T-DM1 therapy. Cancer Biother Radiopharm 34(4):209–217CrossRefGoogle Scholar
  22. 22.
    Balandin TG, Edelweiss E, Andronova NV, Treshalina EM, Sapozhnikov AM, Deyev SM (2011) Antitumor activity and toxicity of anti-HER2 immunoRNase scFv 4D5-dibarnase in mice bearing human breast cancer xenografts. Investig New Drugs 29(1):22–32CrossRefGoogle Scholar
  23. 23.
    Honarvar H, Müller C, Cohrs S, Haller S, Westerlund K, Karlström AE, van der Meulen NP, Schibli R, Tolmachev V (2017) Evaluation of the first 44Sc-labeled Affibody molecule for imaging of HER2-expressing tumors. Nucl Med Biol 45:15–21CrossRefGoogle Scholar
  24. 24.
    Xavier C, Blykers A, Vaneycken I, D'Huyvetter M, Heemskerk J, Lahoutte T, Devoogdt N, Caveliers V (2016) (18)F-nanobody for PET imaging of HER2 overexpressing tumors. Nucl Med Biol 43(4):247–252CrossRefGoogle Scholar
  25. 25.
    Sochaj-Gregorczyk AM, Serwotka-Suszczak AM, Otlewski J (2016) A novel Affibody-Auristatin E conjugate with a potent and selective activity against HER2+ cell lines. J Immunother 39(6):223–232CrossRefGoogle Scholar
  26. 26.
    Jiao H, Zhao X, Liu J, Ma T, Zhang Z, Zhang J, Wang J (2019) In vivo imaging characterization and anticancer efficacy of a novel HER2 affibody and pemetrexed conjugate in lung cancer model. Nucl Med Biol 68–69:31–39CrossRefGoogle Scholar
  27. 27.
    Zhao X, Wang N, Ren X, Zhang J, Wang J, Han J, Jia L, Liu Y, Zhang Z (2014) Preparation and evaluation of (99m)Tc-epidermal growth factor receptor (EGFR)-peptide nucleic acid for visualization of EGFR messenger RNA expression in malignant tumors. J Nucl Med 55(6):1008–1016CrossRefGoogle Scholar
  28. 28.
    Zhang J, Zhao X, Wang S, Wang N, Han J, Jia L, Ren X (2015) Monitoring therapeutic response of human ovarian cancer to trastuzumab by SPECT imaging with (99m)Tc-peptide-Z (HER2:342). Nucl Med Biol 42(6):541–546CrossRefGoogle Scholar
  29. 29.
    Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, Bilous M, Ellis IO, Fitzgibbons P, Hanna W, Jenkins RB, Press MF, Spears PA, Vance GH, Viale G, McShane LM, Dowsett M (2018) Human epidermal growth factor receptor 2 testing in breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 36(20):2105–2122CrossRefGoogle Scholar
  30. 30.
    Postow MA, Callahan MK, Wolchok JD (2015) Immune checkpoint blockade in Cancer therapy. J Clin Oncol 33(17):1974–1982CrossRefGoogle Scholar
  31. 31.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264CrossRefGoogle Scholar
  32. 32.
    Costantini A, Cadranel J (2018) Increased response rates to salvage chemotherapy administered after PD-1/PD-L1 inhibitors in patients with non-small cell lung Cancer. J Thorac Oncol 13(4):e55–e56CrossRefGoogle Scholar
  33. 33.
    Wu SP, Liao RQ, Tu HY, Wang WJ, Dong ZY, Huang SM, Guo WB, Gou LY, Sun HW, Zhang Q, Xie Z, Yan LX, Su J, Yang JJ, Zhong WZ, Zhang XC, Wu YL (2018) Stromal PD-L1-positive regulatory T cells and PD-1-positive CD8-positive T cells define the response of different subsets of non-small cell lung Cancer to PD-1/PD-L1 blockade immunotherapy. J Thorac Oncol 13(4):521–532CrossRefGoogle Scholar
  34. 34.
    Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C (2013) PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 31(23):2895–2902CrossRefGoogle Scholar
  35. 35.
    Liu T, Jin L, Lu W, Gan H, Lin Z, Chen M, Liu J, Zhang F, Wang S, Zhang H, Deng W, Chen H (2019) Sequence-dependent synergistic cytotoxicity of icotinib and pemetrexed in human lung cancer cell line in vitro and in vivo. J Exp Clin Cancer Res 38(1):148CrossRefGoogle Scholar
  36. 36.
    Park JH, Kwon BS, Park SJ, Ji W, Yoon S, Choi CM, Lee JC (2019) Exceptional pemetrexed sensitivity can predict therapeutic benefit from subsequent chemotherapy in metastatic non-squamous non-small cell lung cancer. J Cancer Res Clin Oncol 145(7):1897–1905CrossRefGoogle Scholar
  37. 37.
    Chau CH, Steeg PS, Figg WD (2019) Antibody-drug conjugates for cancer. Lancet 394(10200):793–804CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Nuclear MedicineThe Fourth Hospital of Hebei Medical UniversityShijiazhuangChina
  2. 2.Department of OncologyThe Fourth Hospital of Hebei Medical UniversityShijiazhuangChina

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