Targeting Prostate Cancer with Conditionally Replicative Adenovirus Using PSMA Enhancer

Abstract

Prostate cancer is the second most commonly diagnosed cancer in men and accounts for significant mortality and morbidity in the United States. Initially androgen-dependent, prostate cancer ultimately becomes androgen-independent, which makes the disease extremely difficult to cure. In this study, we examined the use of conditionally replication-competent adenovirus for the treatment of hormone-independent prostate cancer. We utilized PSME, an enhancer element for prostate-specific PSMA expression, to control viral E1A protein expression and achieve exclusive virus replication in prostate. Western blotting confirmed that PSME mediated high E1A protein expression in PSMA-positive, androgen-independent prostate cancer cells (C4-2 and CWR22rv), but was much less active in PSMA-negative cancer cells (PC-3 and A549). Consistent with E1A protein expression, the recombinant adenovirus Ad5-PSME-E1a replicated in C4-2 and CWR22rv almost as efficiently as wild type with low levels of androgen, but its replication was significantly attenuated in PSMA-negative cells. In the in vitro killing assay, Ad5-PSME-E1a lysed all C4-2 and CWR22rv cells 5 days after infection, with minimal effect on PSMA-negative cells. In addition, injections of 1.7 x 10(8) plaque-forming units in a CWR22rv xenograft model in nude mice induced significant tumor growth delay, with a substantial necrotic area. These studies suggest that PSME-driven replication-competent adenovirus may be a new therapeutic modality for prostate cancer patients after hormone ablation therapy.

An oncolytic conditionally replicating adenovirus for hormone-dependent and hormone-independent prostate cancer

“…26 Other CRADs with prostate-specific promoters have been reported. 18,[27][28][29] The CV706 adenovirus, where the E1A gene is under the control of the PSE sequence (the minimal PSA promoter with the upstream PSA enhancer), was used in a phase I clinical trial with a demonstrated good safety profile and therapeutic effects. 19 The PSA promoter is, however, dependent on a functional androgen receptor pathway.…”

“…Recently, a CRAD against prostate cancer has been reported where the E1A gene is under the control of the PSMA enhancer. 29 The PSMA enhancer-controlled CRAD showed good efficacy at low levels of testosterone and it could theoretically be used for prostate cancer patients treated with androgen withdrawal. However, the transcriptional activity of the PSMA enhancer is downregulated at physiological levels of testosterone, which limits the use of the PSMA enhancer-controlled CRAD in patients that are not subject to androgen withdrawal.…”

Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist

“…To investigate the utility of DIMN as a new generation of AR antagonists for the treatment of CRPC, the more aggressive form of prostate cancer, we next determined the inhibitory effect of DIMN on the proliferation of later stage androgenindependent C4 -2 and CWR22rv cells, which grow independently of androgens while expressing AR protein (47,65). The effect of DIMN on the proliferation rate of C4 -2 cells was measured by the MTS assay.…”

Potent anti-tumor activity of telomerase-dependent and HSV-TK armed oncolytic adenovirus for non-small cell lung cancer in vitro and in vivo

“…The advantage of using the replication-competent adenoviruses for therapeutic gene delivery is that it can selectively replicate and spread in malignant tumor tissues, and finally lead to remarkably increased therapeutic gene expression in tumor cells accompanying adenoviral replication and spread. The current strategy to generate tumor-selective replication-competent adenovirus is to replace the adenovirus E1 gene promoter with other tumor or tissue-specific promoter [8,9]. Since human telomerase reverse transcriptase (hTERT) is over-expressed in all types of NSCLC, but is inactivated in normal cells [10], in the present study, we chose the hTERT promoter to drive adenoviral E1A gene expression and generated a tumor-selective replication-competent adenoviral vector.…”