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Targeting prostate cancer with conditionally replicative adenovirus using PSMA enhancer
Sang-Jin Lee1, Yanping Zhang, Sang Don Lee
1Department of Urology, Indiana University, Indianapolis, IN 46202, USA.
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.
Insights
Researchers developed a novel oncolytic adenovirus therapy targeting hormone-independent prostate cancer. This therapy specifically replicates in prostate cancer cells, leading to tumor cell death and significant tumor growth delay in preclinical models.
Area of Science:
- Oncolytic virology
- Prostate cancer therapeutics
- Gene therapy
Background:
- Prostate cancer is a leading cause of cancer death in men.
- Hormone-independent prostate cancer is difficult to treat.
- Targeted therapies are needed for advanced prostate cancer.
Purpose of the Study:
- To investigate the efficacy of a prostate-specific replication-competent adenovirus for treating hormone-independent prostate cancer.
- To evaluate the targeting capability of the engineered adenovirus using a prostate-specific enhancer element (PSME).
Main Methods:
- Constructed a recombinant adenovirus (Ad5-PSME-E1a) with a prostate-specific enhancer (PSME) controlling viral E1A expression.
- Assessed viral replication and E1A protein expression in PSMA-positive and PSMA-negative prostate cancer cell lines.
- Performed in vitro cell killing assays and in vivo xenograft studies in nude mice.
Main Results:
- Ad5-PSME-E1a demonstrated high E1A expression and efficient replication in PSMA-positive prostate cancer cells (C4-2, CWR22rv).
- Replication was significantly attenuated in PSMA-negative cells (PC-3, A549).
- In vitro, Ad5-PSME-E1a effectively lysed prostate cancer cells, with minimal toxicity to PSMA-negative cells.
- In vivo, Ad5-PSME-E1a treatment significantly delayed tumor growth and induced necrosis in a CWR22rv xenograft model.
Conclusions:
- PSME-driven replication-competent adenovirus shows promise as a targeted therapeutic strategy for hormone-independent prostate cancer.
- This approach offers a potential new treatment option for patients who have undergone hormone ablation therapy.
