Retinoblastoma pathway-selective oncolytic adenovirus (RB-selective AdV)

The target refers to a therapeutic strategy utilizing oncolytic adenoviruses engineered for selective replication in cancer cells with a dysregulated Retinoblastoma (RB) pathway (Ramesh et al., 2006, Molecular Therapy). In healthy cells, the RB protein binds to and inhibits E2F transcription factors, preventing the activation of the E2F1 promoter (UniProt P06400). However, in many tumors, the RB pathway is inactivated through various mutations or overactivity of upstream kinases, leading to high levels of free E2F1. By placing the essential viral E1A gene under the control of the E2F1 promoter, the virus is restricted to replicating only in these RB-deficient tumor cells (Burke, 2010, Vaccine). This leads to selective oncolysis, where the virus multiplies within and eventually lyses the cancer cell while sparing normal tissue. This approach is currently being utilized in clinical trials for various malignancies, most notably in non-muscle invasive bladder cancer with agents like Cretostimogene grenadenorepvec (CG0070) (ClinicalTrials.gov NCT04452591).

Other names

E2F1-driven oncolytic adenovirusCG0070E2F1-promoter regulated E1A virusRB-pathway-targeted oncolytic virusCretostimogene grenadenorepvec

Selective viral replication and oncolysis mediated by E2F1-driven expression of the viral E1A gene in cells with a dysfunctional Retinoblastoma (RB) pathway.