Combination of tucatinib and neural stem cells secreting anti-HER2 antibody prolongs survival of mice with metastatic brain cancer.

Abstract

Brain metastases are a leading cause of death in patients with breast cancer. The lack of clinical trials and the presence of the blood-brain barrier limit therapeutic options. Furthermore, overexpression of the human epidermal growth factor receptor 2 (HER2) increases the incidence of breast cancer brain metastases (BCBM). HER2-targeting agents, such as the monoclonal antibodies trastuzumab and pertuzumab, improved outcomes in patients with breast cancer and extracranial metastases. However, continued BCBM progression in breast cancer patients highlighted the need for novel and effective targeted therapies against intracranial metastases. In this study, we engineered the highly migratory and brain tumor tropic human neural stem cells (NSCs) LM008 to continuously secrete high amounts of functional, stable, full-length antibodies against HER2 (anti-HER2Ab) without compromising the stemness of LM008 cells. The secreted anti-HER2Ab impaired tumor cell proliferation in vitro in HER2+ BCBM cells by inhibiting the PI3K-Akt signaling pathway and resulted in a significant benefit when injected in intracranial xenograft models. In addition, dual HER2 blockade using anti-HER2Ab LM008 NSCs and the tyrosine kinase inhibitor tucatinib significantly improved the survival of mice in a clinically relevant model of multiple HER2+ BCBM. These findings provide compelling evidence for the use of HER2Ab-secreting LM008 NSCs in combination with tucatinib as a promising therapeutic regimen for patients with HER2+ BCBM.

• Authors: Alex Cordero, Matthew D Ramsey, Deepak Kanojia, Jawad Fares, Edgar Petrosyan, Charles W Schwartz, Rachel Burga, Peng Zhang, Aida Rashidi, Brandyn Castro, Ting Xiao, Catalina Lee-Chang, Jason Miska, Irina V Balyasnikova, Atique U Ahmed, Maciej S Lesniak
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 119 Issue 1 (01 04 2022) ISSN: 1091-6490 [Electronic] United States
• PMID: 34969858 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 the Author(s). Published by PNAS.

Chemical References

• Antineoplastic Agents, Immunological
• Oxazoles
• Pyridines
• Quinazolines
• tucatinib
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Animals
• Antineoplastic Agents, Immunological (metabolism)
• Brain Neoplasms (genetics, metabolism, pathology, therapy)
• Cell Line, Tumor
• Humans
• Mice
• Mice, Nude
• Neoplasm Metastasis
• Neoplasms, Experimental (genetics, metabolism, pathology, therapy)
• Neural Stem Cells (metabolism, pathology, transplantation)
• Oxazoles (pharmacology)
• Pyridines (pharmacology)
• Quinazolines (pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors, metabolism)
• Xenograft Model Antitumor Assays