Selective targeting of checkpoint kinase 1 in tumor cells with a novel potent oncolytic adenovirus.

DNA-damage checkpoints are activated to arrest cells and promote survival upon genotoxic challenge. Efforts have been taken to target checkpoint kinase 1 (chk1; approved gene symbol CHEK1), a crucial checkpoint modulator, for therapeutic intervention. However, improvement of the potency and specificity of such therapeutics remains a major challenge. This prompted us to develop a novel chk1-targeting strategy by constructing a potent oncolytic adenovirus (M2). M2 was generated by combining two artificial features into a wild-type adenovirus type 5 genome. First, M2 was engineered with a 27-bp deletion in the E1A region to confer tumor-selective replication. Second, an antisense chk1 cDNA was substituted for viral E3 6.7K and gp19K genes. In this design, M2 exploited the adenovirus E3 promoters to express antisense chk1 cDNA in a viral replication-dependent fashion and preferentially silenced the chk1 gene in tumor cells. By virtue of combining oncolysis with chk1 targeting, M2 exhibited potent antitumoral efficacy in vitro and in vivo. Systemic administration of M2, plus a low dose of cisplatin, cured 80% of orthotopic hepatic carcinoma mouse models that were otherwise resistant to cisplatin. These findings have directed us toward the development of novel oncolytic adenoviruses that will be potentially applicable to a wide range of molecular-based therapeutics.