A Conditionally Replicative Adenovirus Vector Containing the SynNotch Receptor Gene for the Treatment of Muscle-invasive Bladder Cancer

Overview

Journal Cancer Gene Ther

Specialties Genetics
Oncology
Pharmacology

Date 2025 Feb 26

PMID 40011711

Authors

Ruhan A

Hideto Ueki

Shunya Nishioka

Rion Yamazaki

Marina Maekawa

Koichi Kitagawa

Hideaki Miyake

Toshiro Shirakawa

Affiliations

Soon will be listed here.

Abstract

Muscle-invasive bladder cancer (MIBC), a highly heterogeneous disease, shows genomic instability and a high mutation rate, making it difficult to treat. Recent studies revealed that cancer stem cells (CSCs) play a critical role in MIBC frequent recurrence and high morbidity. Previous research has shown that Cyclooxygenases-2 (COX-2) is particularly highly expressed in bladder cancer cells. In recent years, the development of oncolytic adenoviruses and their use in clinical trials have gained increased attention. In this study, we composed a conditionally replicative adenovirus vector (CRAd-synNotch) that carries the COX-2 promotor driving adenoviral E1 gene, the synNotch receptor therapeutic gene, and the Ad5/35 fiber gene. Activation of the COX-2 promoter gene causes replication only within COX-2 expressing cancer cells, thereby leading to tumor oncolysis. Also, CD44 and HIF signals contribute to cancer stemness and maintaining CSCs in bladder cancer, and the transduced synNotch receptor inhibits both CD44 and HIF signals simultaneously. We performed an in vivo study using a mouse xenograft model of T24 human MIBC cells and confirmed the significant antitumor activity of CRAd-synNotch. Our findings in this study warrant the further development of CRAd-synNotch for treating patients with MIBC.

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