Effective treatment of ductal carcinoma in situ with a HER-2- targeted alpha-particle emitting radionuclide in a preclinical model of human breast cancer
Metrics: PDF 1952 views | HTML 2455 views | ?
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
Saraswati Sukumar, e-mail: [email protected]
George Sgouros, e-mail: [email protected]
Keywords: intraductal, radioimmunotherapy, trastuzumab, ductal carcinoma in situ, breast cancer
Received: August 05, 2015 Accepted: March 31, 2016 Published: April 23, 2016
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.