title: Neural Stem Cells Secreting Anti-HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases.
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.
authors.affiliation: Brain Tumor Center, The University of Chicago, Illinois, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Kanojia
authors.affiliation: Brain Tumor Center, The University of Chicago, Illinois, USA.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Balyasnikova
authors.affiliation: Brain Tumor Center, The University of Chicago, Illinois, USA.
authors.forename: Ramin A
authors.initials: RA
authors.lastname: Morshed
authors.affiliation: Department of Neurosciences and Division of Neurosurgery, Beckman Research Institute of the City of Hope, Duarte, California, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Frank
authors.affiliation: Brain Tumor Center, The University of Chicago, Illinois, USA.
authors.forename: Dou
authors.initials: D
authors.lastname: Yu
authors.affiliation: Brain Tumor Center, The University of Chicago, Illinois, USA.
authors.forename: Lingjiao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Brain Tumor Center, The University of Chicago, Illinois, USA.
authors.forename: Drew A
authors.initials: DA
authors.lastname: Spencer
authors.affiliation: Brain Tumor Center, The University of Chicago, Illinois, USA.
authors.forename: Julius W
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Brain Tumor Center, The University of Chicago, Illinois, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Molecular and Cellular Oncology, The Univ. Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Dihua
authors.initials: D
authors.lastname: Yu
authors.affiliation: Brain Tumor Center, The University of Chicago, Illinois, USA.
authors.forename: Atique U
authors.initials: AU
authors.lastname: Ahmed
authors.affiliation: Department of Neurosciences and Division of Neurosurgery, Beckman Research Institute of the City of Hope, Duarte, California, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Aboody
authors.affiliation: Brain Tumor Center, The University of Chicago, Illinois, USA.
authors.forename: Maciej S
authors.initials: MS
authors.lastname: Lesniak
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis* / Q000276:immunology; D001812:Blood-Brain Barrier / Q000187:drug effects; D001932:Brain Neoplasms / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D058953:Neural Stem Cells / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000276:immunology; D000068878:Trastuzumab / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000888:Antibodies, Anti-Idiotypic; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: Blood brain barrier; Breast cancer brain metastasis; HER2 overexpressing breast cancer; Human epidermal growth factor receptor 2; Monoclonal antibody therapy; Neural stem cells; Trastuzumab