Anti-EGFR VHH-armed death receptor ligand-engineered allogeneic stem cells have therapeutic efficacy in diverse brain metastatic breast cancers

Basal-like breast cancer (BLBC) shows brain metastatic (BM) capability and overexpresses EGFR and death-receptors 4/5 (DR4/5); however, the anatomical location of BM prohibits efficient drug-delivery to these targetable markers. In this study, we developed BLBC-BM mouse models featuring different pa...

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Bibliographic Details
Published in:Science advances 2021-03, Vol.7 (10)
Main Authors: Kitamura, Yohei, Kanaya, Nobuhiko, Moleirinho, Susana, Du, Wanlu, Reinshagen, Clemens, Attia, Nada, Bronisz, Agnieszka, Revai Lechtich, Esther, Sasaki, Hikaru, Mora, Joana Liliana, Brastianos, Priscilla Kaliopi, Falcone, Jefferey L, Hofer, Aldebaran M, Franco, Arnaldo, Shah, Khalid
Format: Article
Language:English
Subjects:
Animals
Brain - metabolism
Brain Neoplasms - therapy
Breast Neoplasms - pathology
Cancer
Cell Biology
Cell Line, Tumor
Developmental Biology
ErbB Receptors - genetics
Female
Hematopoietic Stem Cell Transplantation
Humans
Ligands
Mice
Receptors, Death Domain - metabolism
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Summary:Basal-like breast cancer (BLBC) shows brain metastatic (BM) capability and overexpresses EGFR and death-receptors 4/5 (DR4/5); however, the anatomical location of BM prohibits efficient drug-delivery to these targetable markers. In this study, we developed BLBC-BM mouse models featuring different patterns of BMs and explored the versatility of estem cell (SC)-mediated bi-functional EGFR and DR4/5-targeted treatment in these models. Most BLBC lines demonstrated a high sensitivity to EGFR and DR4/5 bi-targeting therapeutic protein, E DR [anti-EGFR VHH (E ) fused to DR ligand (DR )]. Functional analyses using inhibitors and CRISPR-Cas9 knockouts revealed that the E domain facilitated in augmenting DR4/5-DR binding and enhancing DR -induced apoptosis. E DR secreting stem cells alleviated tumor-burden and significantly increased survival in mouse models of residual-tumor after macrometastasis resection, perivascular niche micrometastasis, and leptomeningeal metastasis. This study reports mechanism based simultaneous targeting of EGFR and DR4/5 in BLBC and defines a new treatment paradigm for treatment of BM.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abe8671