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

Yohei Kitamura, Nobuhiko Kanaya, Susana Moleirinho, Wanlu Du, Clemens Reinshagen, Nada Attia, Agnieszka Bronisz, Esther Revai Lechtich, Hikaru Sasaki, Joana Liliana Mora, Priscilla Kaliopi Brastianos, Jefferey L. Falcone, Aldebaran M. Hofer, Arnaldo Franco, Khalid Shah

研究成果: Article査読

抄録

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, EVDRL [anti-EGFR VHH (EV) fused to DR ligand (DRL)]. Functional analyses using inhibitors and CRISPR-Cas9 knockouts revealed that the EV domain facilitated in augmenting DR4/5-DRL binding and enhancing DRL-induced apoptosis. EVDRL 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.

本文言語English
論文番号eabe8671
ジャーナルScience Advances
7
10
DOI
出版ステータスPublished - 2021 3 3

ASJC Scopus subject areas

  • General

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