Oncotarget

Research Papers:

Effective treatment of ductal carcinoma in situ with a HER-2- targeted alpha-particle emitting radionuclide in a preclinical model of human breast cancer

Takahiro Yoshida, Kideok Jin, Hong Song, Sunju Park, David L. Huso, Zhe Zhang, Han Liangfeng, Charles Zhu, Frank Bruchertseifer, Alfred Morgenstern, George Sgouros and Saraswati Sukumar _

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Oncotarget. 2016; 7:33306-33315. https://doi.org/10.18632/oncotarget.8949

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Abstract

Takahiro Yoshida1,*,$, Kideok Jin1,*, Hong Song2, Sunju Park1, David L. Huso3,@, Zhe Zhang1, Han Liangfeng1, Charles Zhu4, Frank Bruchertseifer5, Alfred Morgenstern5, George Sgouros2, Saraswati Sukumar1

1Department of Oncology, Johns Hopkins University School of Medicine, Maryland, USA

2Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Maryland, USA

3Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Maryland, USA

4Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA

5European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, Germany

$Current address: Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, Japan

*These authors have contributed equally to this work

@Deceased

Correspondence to:

Saraswati Sukumar, e-mail: saras@jhmi.edu

George Sgouros, e-mail: gsgouros@jhmi.edu

Keywords: intraductal, radioimmunotherapy, trastuzumab, ductal carcinoma in situ, breast cancer

Received: August 05, 2015     Accepted: March 31, 2016     Published: April 23, 2016

ABSTRACT

The standard treatment for ductal carcinoma in situ (DCIS) of the breast is surgical resection, followed by radiation. Here, we tested localized therapy of DCIS in mice using the immunoconjugate 225Ac linked-trastuzumab delivered through the intraductal (i.duc) route. Trastuzumab targets HER-2/neu, while the alpha-emitter 225Ac (half-life, 10 days) delivers highly cytotoxic, focused doses of radiation to tumors. Systemic 225Ac, however, elicits hematologic toxicity and at high doses free 213Bi, generated by its decay, causes renal toxicity. I.duc delivery of the radioimmunoconjugate could bypass its systemic toxicity. Bioluminescent imaging showed that the therapeutic efficacy of intraductal 225Ac-trastuzumab (10-40 nCi per mammary gland; 30-120 nCi per mouse) in a DCIS model of human SUM225 cancer cells in NSG mice was significantly higher (p<0.0003) than intravenous (120 nCi per mouse) administration, with no kidney toxicity or loss of body weight. Our findings suggest that i.duc radioimmunotherapy using 225Ac-trastuzumab deserves greater attention for future clinical development as a treatment modality for early breast cancer.


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