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Sci Rep. 2017 Jun 1;7(1):2602. doi: 10.1038/s41598-017-02483-9.

Bi-specific molecule against EGFR and death receptors simultaneously targets proliferation and death pathways in tumors.

Zhu Y1,2, Bassoff N1,2, Reinshagen C1,3,2,4, Bhere D1,3,2,4, Nowicki MO4, Lawler SE4, Roux J5, Shah K6,7,8,9,10,11.

Author information

1
Center for Stem Cell Therapeutics and Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02114, USA.
2
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02114, USA.
3
Center for Stem Cell Therapeutics and Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA.
4
Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA.
5
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, 02115, USA.
6
Center for Stem Cell Therapeutics and Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02114, USA. kshah@bwh.harvard.edu.
7
Center for Stem Cell Therapeutics and Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA. kshah@bwh.harvard.edu.
8
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02114, USA. kshah@bwh.harvard.edu.
9
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02114, USA. kshah@bwh.harvard.edu.
10
Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA. kshah@bwh.harvard.edu.
11
Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, 02138, USA. kshah@bwh.harvard.edu.

Abstract

Developing therapeutics that target multiple receptor signaling pathways in tumors is critical as therapies targeting single specific biomarker/pathway have shown limited efficacy in patients with cancer. In this study, we extensively characterized a bi-functional molecule comprising of epidermal growth factor receptor (EGFR) targeted nanobody (ENb) and death receptor (DR) targeted ligand TRAIL (ENb-TRAIL). We show that ENb-TRAIL has therapeutic efficacy in tumor cells from different cancer types which do not respond to either EGFR antagonist or DR agonist monotherapies. Utilizing pharmacological inhibition, genetic loss of function and FRET studies, we show that ENb-TRAIL blocks EGFR signalling via the binding of ENb to EGFR which in turn induces DR5 clustering at the plasma membrane and thereby primes tumor cells to caspase-mediated apoptosis. In vivo, using a clinically relevant orthotopic resection model of primary glioblastoma and engineered stem cells (SC) expressing ENb-TRAIL, we show that the treatment with synthetic extracellular matrix (sECM) encapsulated SC-ENb-TRAIL alleviates tumor burden and significantly increases survival. This study is the first to report novel mechanistic insights into simultaneous targeting of receptor-mediated proliferation and cell death signaling pathways in different tumor types and presents a promising approach for translation into the clinical setting.

PMID:
28572590
PMCID:
PMC5454031
DOI:
10.1038/s41598-017-02483-9
[Indexed for MEDLINE]
Free PMC Article

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