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

Autor: Kitamura Y; Center for Stem Cell Therapeutics and Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Kanaya N; Center for Stem Cell Therapeutics and Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Moleirinho S; Center for Stem Cell Therapeutics and Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Du W; Center for Stem Cell Therapeutics and Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Reinshagen C; Center for Stem Cell Therapeutics and Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Attia N; Center for Stem Cell Therapeutics and Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Bronisz A; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Revai Lechtich E; Center for Stem Cell Therapeutics and Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Sasaki H; Department of Neurosurgery, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan., Mora JL; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA., Brastianos PK; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA., Falcone JL; VA Boston Healthcare System, Brigham and Women's Hospital, Harvard Medical School, West Roxbury, MA 02132, USA., Hofer AM; VA Boston Healthcare System, Brigham and Women's Hospital, Harvard Medical School, West Roxbury, MA 02132, USA., Franco A; Center for Stem Cell Therapeutics and Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Shah K; Center for Stem Cell Therapeutics and Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. kshah@bwh.harvard.edu.; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2021 Mar 03; Vol. 7 (10). Date of Electronic Publication: 2021 Mar 03 (Print Publication: 2021).
DOI: 10.1126/sciadv.abe8671
Abstrakt: 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 V DR L [anti-EGFR VHH (E V ) fused to DR ligand (DR L )]. Functional analyses using inhibitors and CRISPR-Cas9 knockouts revealed that the E V domain facilitated in augmenting DR4/5-DR L binding and enhancing DR L -induced apoptosis. E V DR L 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.
(Copyright © 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).)
Databáze: MEDLINE
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