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Viral transduction of the HER2-extracellular domain expands trastuzumab-based photoimmunotherapy for HER2-negative breast cancer cells

Abstract

The prognosis of HER2-positive breast cancer has been improved by trastuzumab therapy, which features high specificity and limited side effects. However, trastuzumab-based therapy has shortcomings. Firstly, HER2-targeted therapy is only applicable to HER2-expressing tumors, which comprise only 20–25 % of primary breast cancers. Secondly, many patients who initially respond to trastuzumab ultimately develop disease progression. To overcome these problems, we employed virus-mediated HER2 transduction and photoimmunotherapy (PIT) which involves trastuzumab conjugated with a photosensitizer, trastuzumab-IR700, and irradiation of near-infrared light. We hypothesized that the gene transduction technique together with PIT would expand the range of tumor entities suitable for trastuzumab-based therapy and improve its antitumor activity. The HER2-extracellular domain (ECD) was transduced by the adenoviral vector, Ad-HER2-ECD, and PIT with trastuzumab-IR700 was applied in the HER2-negative cancer cells. Ad-HER2-ECD can efficiently transduce HER2-ECD into HER2-negative human cancer cells. PIT with trastuzumab-IR700 induced direct cell membrane destruction of Ad-HER2-ECD-transduced HER2-negative cancer cells. Novel combination of viral transduction of a target antigen and an antibody-based PIT would expand and potentiate molecular-targeted therapy even for target-negative or attenuated cancer cells.

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Abbreviations

DMEM:

Dulbecco’s modified Eagle’s medium

ECD:

Extracellular domain

HER2:

Human epidermal growth factor receptor type 2

MOI:

A multiplicity of infection

NIR:

Near infrared

PBS:

Phosphate-buffered saline

PI:

Propidium iodide

PIT:

Photoimmunotherapy

SDS:

Sodium dodecyl sulfate

SQ:

Self-quenched

Tra-IR700:

Trastuzumab-IR700

XTT:

The sodium 3′-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro) benzene sulfonic acid hydrate

References

  1. 1.

    Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science (New York, N.Y.) 244:707–712

  2. 2.

    Dawood S, Broglio K, Buzdar AU, Hortobagyi GN, Giordano SH (2010) Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol 28:92–98. doi:10.1200/jco.2008.19.9844

  3. 3.

    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182

  4. 4.

    Carlsson J, Nordgren H, Sjostrom J, Wester K, Villman K, Bengtsson NO, Ostenstad B, Lundqvist H, Blomqvist C (2004) HER2 expression in breast cancer primary tumours and corresponding metastases. Original data and literature review. Br J Cancer 90:2344–2348. doi:10.1038/sj.bjc.6601881

  5. 5.

    Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ (2006) Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol 3:269–280. doi:10.1038/ncponc0509

  6. 6.

    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792. doi:10.1056/nejm200103153441101

  7. 7.

    Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J (2011) Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365:1273–1283. doi:10.1056/NEJMoa0910383

  8. 8.

    Mitsunaga M, Ogawa M, Kosaka N, Rosenblum LT, Choyke PL, Kobayashi H (2011) Cancer cell-selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules. Nat Med 17:1685–1691. doi:10.1038/nm.2554

  9. 9.

    Yoshida R, Tazawa H, Hashimoto Y, Yano S, Onishi T, Sasaki T, Shirakawa Y, Kishimoto H, Uno F, Nishizaki M, Kagawa S, Fujiwara T (2012) Mechanism of resistance to trastuzumab and molecular sensitization via ADCC activation by exogenous expression of HER2-extracellular domain in human cancer cells. Cancer Immunol Immunother 61:1905–1916. doi:10.1007/s00262-012-1249-x

  10. 10.

    Umeoka T, Kawashima T, Kagawa S, Teraishi F, Taki M, Nishizaki M, Kyo S, Nagai K, Urata Y, Tanaka N, Fujiwara T (2004) Visualization of intrathoracically disseminated solid tumors in mice with optical imaging by telomerase-specific amplification of a transferred green fluorescent protein gene. Cancer research 64:6259–6265. doi:10.1158/0008-5472.can-04-1335

  11. 11.

    Kagawa S, He C, Gu J, Koch P, Rha SJ, Roth JA, Curley SA, Stephens LC, Fang B (2001) Antitumor activity and bystander effects of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene. Cancer Res 61:3330–3338

  12. 12.

    Papanikolaou V, Iliopoulos D, Dimou I, Dubos S, Tsougos I, Theodorou K, Kitsiou-Tzeli S, Tsezou A (2009) The involvement of HER2 and p53 status in the regulation of telomerase in irradiated breast cancer cells. Int J Oncol 35:1141–1149

  13. 13.

    Sledge GW, Mamounas EP, Hortobagyi GN, Burstein HJ, Goodwin PJ, Wolff AC (2014) Past, present, and future challenges in breast cancer treatment. J Clin Oncol. doi:10.1200/jco.2014.55.4139

  14. 14.

    Subik K, Lee JF, Baxter L, Strzepek T, Costello D, Crowley P, Xing L, Hung MC, Bonfiglio T, Hicks DG, Tang P (2010) The Expression Patterns of ER, PR, HER2, CK5/6, EGFR, Ki-67 and AR by Immunohistochemical Analysis in Breast Cancer Cell Lines. Breast Cancer 4:35–41

  15. 15.

    Hudziak RM, Lewis GD, Winget M, Fendly BM, Shepard HM, Ullrich A (1989) p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol 9:1165–1172

  16. 16.

    Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blattler WA, Lambert JM, Chari RV, Lutz RJ, Wong WL, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD, Sliwkowski MX (2008) Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 68:9280–9290. doi:10.1158/0008-5472.can-08-1776

  17. 17.

    Nakajima T, Sano K, Mitsunaga M, Choyke PL, Kobayashi H (2012) Real-time monitoring of in vivo acute necrotic cancer cell death induced by near infrared photoimmunotherapy using fluorescence lifetime imaging. Cancer Res 72:4622–4628. doi:10.1158/0008-5472.can-12-1298

  18. 18.

    Mitsunaga M, Nakajima T, Sano K, Kramer-Marek G, Choyke PL, Kobayashi H (2012) Immediate in vivo target-specific cancer cell death after near infrared photoimmunotherapy. BMC Cancer 12:345. doi:10.1186/1471-2407-12-345

  19. 19.

    Sano K, Mitsunaga M, Nakajima T, Choyke PL, Kobayashi H (2012) In vivo breast cancer characterization imaging using two monoclonal antibodies activatably labeled with near infrared fluorophores. Breast Cancer Res 14:R61. doi:10.1186/bcr3167

  20. 20.

    Sliwkowski MX, Lofgren JA, Lewis GD, Hotaling TE, Fendly BM, Fox JA (1999) Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol 26:60–70

  21. 21.

    Hudis CA (2007) Trastuzumab–mechanism of action and use in clinical practice. N Engl J Med 357:39–51. doi:10.1056/NEJMra043186

  22. 22.

    Berg K, Weyergang A, Prasmickaite L, Bonsted A, Hogset A, Strand MT, Wagner E, Selbo PK (2010) Photochemical internalization (PCI): a technology for drug delivery. Methods Mol Biol 635:133–145. doi:10.1007/978-1-60761-697-9_10

  23. 23.

    Berstad MB, Weyergang A, Berg K (2012) Photochemical internalization (PCI) of HER2-targeted toxins: synergy is dependent on the treatment sequence. Biochim Biophys Acta 1820:1849–1858. doi:10.1016/j.bbagen.2012.08.027

  24. 24.

    Owen SC, Patel N, Logie J, Pan G, Persson H, Moffat J, Sidhu SS, Shoichet MS (2013) Targeting HER2 + breast cancer cells: lysosomal accumulation of anti-HER2 antibodies is influenced by antibody binding site and conjugation to polymeric nanoparticles. J Control Release 172:395–404. doi:10.1016/j.jconrel.2013.07.011

  25. 25.

    Shirasu N, Yamada H, Shibaguchi H, Kuroki M, Kuroki M (2014) Potent and specific antitumor effect of CEA-targeted photoimmunotherapy. Int J Cancer. doi:10.1002/ijc.28907

  26. 26.

    Garrett JT, Arteaga CL (2011) Resistance to HER2-directed antibodies and tyrosine kinase inhibitors: mechanisms and clinical implications. Cancer Biol Ther 11:793–800

  27. 27.

    Zhang S, Huang WC, Li P, Guo H, Poh SB, Brady SW, Xiong Y, Tseng LM, Li SH, Ding Z, Sahin AA, Esteva FJ, Hortobagyi GN, Yu D (2011) Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med 17:461–469. doi:10.1038/nm.2309

  28. 28.

    Burris HA 3rd, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S, Tan-Chiu E, Krop IE, Michaelson RA, Girish S, Amler L, Zheng M, Chu YW, Klencke B, O’Shaughnessy JA (2011) Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 29:398–405. doi:10.1200/jco.2010.29.5865

  29. 29.

    Junutula JR, Flagella KM, Graham RA, Parsons KL, Ha E, Raab H, Bhakta S, Nguyen T, Dugger DL, Li G, Mai E, Lewis Phillips GD, Hiraragi H, Fuji RN, Tibbitts J, Vandlen R, Spencer SD, Scheller RH, Polakis P, Sliwkowski MX (2010) Engineered thio-trastuzumab-DM1 conjugate with an improved therapeutic index to target human epidermal growth factor receptor 2-positive breast cancer. Clinical Cancer Res 16:4769–4778. doi:10.1158/1078-0432.ccr-10-0987

  30. 30.

    Weissleder R (2001) A clearer vision for in vivo imaging. Nat Non-viral Biotechnol 19:316–317. doi:10.1038/86684

  31. 31.

    Mitsunaga M, Nakajima T, Sano K, Choyke PL, Kobayashi H (2012) Near-infrared theranostic photoimmunotherapy (PIT): repeated exposure of light enhances the effect of immunoconjugate. Bioconjugate Chem 23:604–609. doi:10.1021/bc200648m

  32. 32.

    Sano K, Nakajima T, Choyke PL, Kobayashi H (2014) The effect of photoimmunotherapy followed by liposomal daunorubicin in a mixed tumor model: a demonstration of the super-enhanced permeability and retention effect after photoimmunotherapy. Mol Cancer Ther 13:426–432. doi:10.1158/1535-7163.mct-13-0633

  33. 33.

    Schuler M, Herrmann R, De Greve JL, Stewart AK, Gatzemeier U, Stewart DJ, Laufman L, Gralla R, Kuball J, Buhl R, Heussel CP, Kommoss F, Perruchoud AP, Shepherd FA, Fritz MA, Horowitz JA, Huber C, Rochlitz C (2001) Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: results of a multicenter phase II study. J Clin Oncol 19:1750–1758

  34. 34.

    Smith E, Breznik J, Lichty BD (2011) Strategies to enhance viral penetration of solid tumors. Hum Gene Ther 22:1053–1060. doi:10.1089/hum.2010.227

  35. 35.

    Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, Anderson DG (2014) vectors for gene-based therapy. Nature reviews. Genetics 15:541–555. doi:10.1038/nrg3763

  36. 36.

    Kishimoto H, Kojima T, Watanabe Y, Kagawa S, Fujiwara T, Uno F, Teraishi F, Kyo S, Mizuguchi H, Hashimoto Y, Urata Y, Tanaka N, Fujiwara T (2006) In vivo imaging of lymph node metastasis with telomerase-specific replication-selective adenovirus. Nat Med 12:1213–1219. doi:10.1038/nm1404

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Acknowledgments

We thank Tomoko Sueishi for her technical support. This study was supported by grants-in-aid from the Ministry of Education Culture, Sports, Science and Technology, Japan (Toshiyoshi Fujiwara, Hiroshi Tazawa, Shunsuke Tanabe, and Shunsuke Kagawa) and grants from the Ministry of Health, Labor and Welfare, Japan (Toshiyoshi Fujiwara).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Correspondence to Shunsuke Kagawa.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Morphological change induced immediately after Tra-IR700 mediated PIT in HER2-ECD transduced breast cancer cells captured as a time-lapse movie (MP4 4920 kb)

The cellular membrane injury that was caused in 1. MDA-MD-231 cells and 2. MCF7 cells immediately after Tra-IR700 mediated PIT is shown (MP4 4644 kb)

Morphological change induced immediately after Tra-IR700 mediated PIT in HER2-ECD transduced breast cancer cells captured as a time-lapse movie (MP4 4920 kb)

The cellular membrane injury that was caused in 1. MDA-MD-231 cells and 2. MCF7 cells immediately after Tra-IR700 mediated PIT is shown (MP4 4644 kb)

Fig. S1

Adenoviral transduction of GFP protein into breast cancer cells. Fluorescence microscopic analysis of (a) MCF7 cells and (b) MDA-MB-231 cells that were transduced with GFP using Ad-GFP at the indicated MOIs. Most cells were transduced with GFP at an Ad-GFP MOI of 50 (PPT 468 kb)

Fig. S2

Microscopic analysis of the effect of Tra-IR700 mediated PIT on Saos2 cells infected with Ad-HER2-ECD. (a) Phase contrast analysis of the morphology of Ad-HER2-ECD-infected Saos2 cells immediately after PIT using 6 J or 24 J, and 24 h after PIT using 24 J. (b) PI staining of Ad-HER2-ECD-infected Saos2 cells 5 days after Tra-IR700 mediated PIT using 15 J. PI staining indicates plasma membrane destruction of Saos2 cells following treatment (PPT 284 kb)

Fig. S3

Effect of Tra-IR700-mediated PIT on cell viability of SK-BR-3 and Saos2 cells. (a) HER2-positive SK-BR-3 cells were treated with trastuzumab or with Tra-IR700 in combination with NIR irradiation as indicated and cell viability was measured using the XTT assay after 72h. The suppression of cell viability by Tra-IR1700 plus NIR (24 J) was significantly higher than that induced by trastuzumab or by any of the control groups. (b) Saos2 cells transduced with Ad-HER2-ECD were treated with Tra-IR700 mediated PIT () or with seven control conditions and cell viability was quantified after 72h using the XTT assay. Only the Ad-HER2-ECD transduced cells treated with Tra-IR700-mediated PIT (24 J) showed cell death that was significantly higher than that induced in any of the other groups (PPT 141 kb)

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Shimoyama, K., Kagawa, S., Ishida, M. et al. Viral transduction of the HER2-extracellular domain expands trastuzumab-based photoimmunotherapy for HER2-negative breast cancer cells. Breast Cancer Res Treat 149, 597–605 (2015). https://doi.org/10.1007/s10549-015-3265-y

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Keywords

  • Photoimmunotherapy
  • HER2
  • Breast cancer
  • Adenovirus