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

Abstract
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.
AuthorsYohei 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
JournalScience advances (Sci Adv) Vol. 7 Issue 10 (03 2021) ISSN: 2375-2548 [Electronic] United States
PMID33658202 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
Chemical References
  • Ligands
  • Receptors, Death Domain
  • ErbB Receptors
Topics
  • Animals
  • Brain (metabolism)
  • Brain Neoplasms (therapy)
  • Breast Neoplasms (pathology)
  • Cell Line, Tumor
  • ErbB Receptors (genetics)
  • Female
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Ligands
  • Mice
  • Receptors, Death Domain (metabolism)

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