Therapeutic stem cells expressing variants of EGFR-specific nanobodies have antitumor effects.

in Proceedings of the National Academy of Sciences of the United States of America by Jeroen A J M van de Water, Tugba Bagci-Onder, Aayush S Agarwal, Hiroaki Wakimoto, Rob C Roovers, Yanni Zhu, Randa Kasmieh, Deepak Bhere, Paul M P Van Bergen en Henegouwen, Khalid Shah

TLDR

  • The study is trying to find a new way to treat a type of brain tumor called glioblastoma multiforme (GBM). They are using a type of protein called nanobodies (ENb) that can target a specific protein called EGFR. They are also using a protein called TRAIL to help kill the cancer cells. They are releasing these proteins from special cells called stem cells (SCs) and testing them in mice to see if they work. The study shows that the proteins specifically target the tumor and help kill the cancer cells. They also show that the proteins can be used in a new type of treatment for GBM that could be helpful for people with this type of cancer.

Abstract

The deregulation of the epidermal growth factor receptor (EGFR) has a significant role in the progression of tumors. Despite the development of a number of EGFR-targeting agents that can arrest tumor growth, their success in the clinic is limited in several tumor types, particularly in the highly malignant glioblastoma multiforme (GBM). In this study, we generated and characterized EGFR-specific nanobodies (ENb) and imageable and proapoptotic ENb immunoconjugates released from stem cells (SC) to ultimately develop a unique EGFR-targeted therapy for GBM. We show that ENbs released from SCs specifically localize to tumors, inhibit EGFR signaling resulting in reduced GBM growth and invasiveness in vitro and in vivo in both established and primary GBM cell lines. We also show that ENb primes GBM cells for proapoptotic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Furthermore, SC-delivered immunoconjugates of ENb and TRAIL target a wide spectrum of GBM cell types with varying degrees of TRAIL resistance and significantly reduce GBM growth and invasion in both established and primary invasive GBM in mice. This study demonstrates the efficacy of SC-based EGFR targeted therapy in GBMs and provides a unique approach with clinical implications.

Overview

  • The study aims to develop a unique EGFR-targeted therapy for GBM using ENb released from SCs. The study generates and characterizes ENbs and immunoconjugates of ENb and TRAIL released from SCs. The study shows that ENbs specifically localize to tumors, inhibit EGFR signaling, and prime GBM cells for TRAIL-induced apoptosis. The study also demonstrates the efficacy of SC-based EGFR targeted therapy in GBMs and provides a unique approach with clinical implications.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions. The study shows that ENbs released from SCs specifically localize to tumors, inhibit EGFR signaling, and prime GBM cells for TRAIL-induced apoptosis. The study also demonstrates the efficacy of SC-based EGFR targeted therapy in GBMs and provides a unique approach with clinical implications.

Implications and Future Directions

  • The study's findings suggest that SC-based EGFR targeted therapy could be a promising approach for the treatment of GBM. The study identifies the need for further research to optimize the delivery of ENb and TRAIL immunoconjugates and to evaluate their safety and efficacy in clinical trials. The study also suggests that SC-based EGFR targeted therapy could be applied to other tumor types with EGFR overexpression.
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