Abstract
Adenoviral gene therapy using the death receptor ligand TRAIL as the therapeutic transgene can be safely administered via intraprostatic injection but has not been evaluated for efficacy in patients. Here we investigated the efficacy of adenoviral TRAIL gene therapy in a model of castration resistant prostate cancer and found that intratumoral injections can significantly delay tumor growth but cannot eliminate established lesions. We hypothesized that an underlying cause is inefficient adenoviral delivery. Using the LNCaP progression model of prostate cancer we show that surface CAR expression decreases with increasing tumorigenicity and that castration resistant C4-2b cells were more difficult to transduce with adenovirus than castration sensitive LNCaP cells. Many genes, including CAR, are epigenetically silenced during transformation but a new class of chemotherapeutic agents, known as histone deacetylase inhibitors (HDACi), can reverse this process. We demonstrate that HDACi restore CAR expression and infectivity in C4-2b cells and enhance caspase activation in response to infection with a TRAIL adenovirus. We also show that in cells with high surface CAR expression, HDACi further enhance transgene expression from the CMV promoter. Thus HDACi have multiple beneficial effects, which may enhance not only viral but also non-viral gene therapy of castration resistant prostate cancer.
Highlights
Epigenetic alterations, such as aberrant activity of histone deacetylases, are frequently observed in malignancies
We have previously shown that the histone deacetylase inhibitors (HDACi) romidepsin and MS-275, which are both under investigation for their therapeutic potential against prostate cancer, can selectively enhance adenovirusexpressing membrane TRAIL (AdTRAIL) gene therapy in castration-sensitive LNCaP cells and that an increase in coxsackie and adenovirus receptor (CAR) expression contributed to this effect [3]
We propose that maximum efficacy against advanced prostate cancer can be safely achieved by combining HDACi with TRAIL gene therapy using conditionally replicative adenovirus (CRAd)
Summary
Epigenetic alterations, such as aberrant activity of histone deacetylases, are frequently observed in malignancies. Using two HDACi under evaluation for the treatment of prostate cancer, we previously demonstrated that both romidepsin ( known as depsipeptide) and MS-275 enhanced the in vitro efficacy of adenoviral TRAIL gene therapy in castration-sensitive LNCaP prostate cancer cells [3]. This effect was selective for the malignant cells as primary cultures of prostate epithelial cells were not adversely affected [3]
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