Neural Stem Cells Secreting Anti‐HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases. (11th August 2015)

• Record Type: Journal Article
• Authors: Kanojia, Deepak; Balyasnikova, Irina V.; Morshed, Ramin A.; Frank, Richard T.; Yu, Dou; Zhang, Lingjiao; Spencer, Drew A.; Kim, Julius W.; Han, Yu; Yu, Dihua; Ahmed, Atique U.; Aboody, Karen S.; Lesniak, Maciej S.
• Is Part Of: Stem cells. Volume 33:Number 10(2015:Oct.)
• Page Start: 2985
• Page End: 2994
• Publication Date: 2015-08-11
• Subjects: Neural stem cells -- Breast cancer brain metastasis -- Human epidermal growth factor receptor 2 -- HER2 overexpressing breast cancer -- Trastuzumab -- Blood brain barrier -- Monoclonal antibody therapy; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2109
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: The treatment of human epidermal growth factor receptor 2 (HER2)‐overexpressing breast cancer has been revolutionized by trastuzumab. However, longer survival of these patients now predisposes them to forming HER2 positive brain metastases, as the therapeutic antibodies cannot cross the blood brain barrier. The current oncologic repertoire does not offer a rational, nontoxic targeted therapy for brain metastases. In this study, we used an established human neural stem cell line, HB1.F3 NSCs and generated a stable pool of cells secreting a high amount of functional full‐length anti‐HER2 antibody, equivalent to trastuzumab. Anti‐HER2Ab secreted by the NSCs (HER2Ab‐NSCs) specifically binds to HER2 overexpressing human breast cancer cells and inhibits PI3K‐Akt signaling. This translates to HER2Ab‐NSC inhibition of breast cancer cell growth in vitro. Preclinical in vivo experiments using HER2Ab overexpressing NSCs in a breast cancer brain metastases (BCBM) mouse model demonstrate that intracranial injection of HER2Ab‐NSCs significantly improves survival. In effect, these NSCs provide tumor localized production of HER2Ab, minimizing any potential off‐target side effects. Our results establish HER2Ab‐NSCs as a novel, nontoxic, and rational therapeutic approach for the successful treatment of HER2 overexpressing BCBM, which now warrants further preclinical and clinical investigation. Stem Cells 2015;33:2985–2994 Abstract : Production of anti‐HER2 antibodies (red) by neural stem cells and their binding (yellow arrows) to the surface of HER2‐positive brain metastatic breast cancer cells (green).