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

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

doi:10.1126/sciadv.abe8671

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.

Highlights

Breast cancer (BC) is the second most common cancer that can metastasize to the brain and, brain metastasis (BM) is a major cause of cancer-related deaths in patients with BC
Immunohistochemistry of triple-negative breast cancer (TNBC) patient samples showed that BM tissue displayed a significantly higher expression of epidermal growth factor receptor (EGFR) compared to the primary tumor
We developed different imageable mouse models of BLBCBM and explored the versatility of stem cell–mediated bi-functional EGFR and death-receptors 4/5 (DR4/5) therapeutics in these models

Summary

Introduction

Breast cancer (BC) is the second most common cancer that can metastasize to the brain and, brain metastasis (BM) is a major cause of cancer-related deaths in patients with BC. Along with the increase in the incidence of BC [3], the occurrence of BC-BM has increased in recent years owing to improved extracranial disease control and poor central nervous system (CNS) penetration of drugs [4]. BLBC has the poorest prognosis and the shortest survival among the BC subtypes [6], owing to the unavailability of specific therapeutic options including hormonal or molecular-targeted therapy. BLBC metastasizes to the brain more frequently than the other subtypes [7, 8], shortening patient survival [9]

Methods

Results

Conclusion