Neural Stem Cells Secreting Anti-HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases

Deepak Kanojia, Irina V. Balyasnikova, Ramin A. Morshed, Richard T. Frank, Dou Yu, Lingjiao Zhang, Drew A. Spencer, Julius W. Kim, Yu Han, Dihua Yu, Atique U. Ahmed, Karen S. Aboody, Maciej S. Lesniak*

*Corresponding author for this work

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2985-2994
Number of pages10
JournalStem Cells
Volume33
Issue number10
DOIs
StatePublished - Jan 1 2015

Fingerprint

Neural Stem Cells
Brain Neoplasms
Breast Neoplasms
Neoplasm Metastasis
Survival
Antibodies
Therapeutics
Brain
Blood-Brain Barrier
Phosphatidylinositol 3-Kinases
human ERBB2 protein
Cell Line
Injections
Growth
Neoplasms

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

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. / Neural Stem Cells Secreting Anti-HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases. In: Stem Cells. 2015 ; Vol. 33, No. 10. pp. 2985-2994.
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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.",
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Neural Stem Cells Secreting Anti-HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases. / 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.

In: Stem Cells, Vol. 33, No. 10, 01.01.2015, p. 2985-2994.

Research output: Contribution to journalArticle

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T1 - Neural Stem Cells Secreting Anti-HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases

AU - Kanojia, Deepak

AU - Balyasnikova, Irina V.

AU - Morshed, Ramin A.

AU - Frank, Richard T.

AU - Yu, Dou

AU - Zhang, Lingjiao

AU - Spencer, Drew A.

AU - Kim, Julius W.

AU - Han, Yu

AU - Yu, Dihua

AU - Ahmed, Atique U.

AU - Aboody, Karen S.

AU - Lesniak, Maciej S.

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KW - Breast cancer brain metastasis

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KW - Monoclonal antibody therapy

KW - Neural stem cells

KW - Trastuzumab

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