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Abstract
Localized prostate cancer (PCa) is often curable, whereas metastatic disease treated by castration inevitably progresses toward castration-resistant PCa (CRPC). Most CRPC treatments target androgen receptor (AR) signaling. However, not all CRPC cells rely on AR activity for survival and proliferation. With advances in immunotherapy and fluid biopsies for cancer management, expression systems specific for both AR-positive and -negative PCa are required for virus-based vaccines and cell imaging. To target both AR-responsive and non-responsive cells, we developed a three-step transcriptional amplification (3STA) system based on the progression elevated gene-3 (PEG3) promoter named PEG3AP1-3STA. Notably, we report on different genetic modifications that significantly improved PEG3 promoter’s strength in PCa cells. Adenoviruses incorporating PEG3 promoter with and without transcriptional amplification systems were generated. The potential of PEG3AP1-3STA to target PCa cells was then evaluated in vitro and in vivo in androgen-responsive and non-responsive PCa cell lines. PEG3AP1-3STA was shown to be active in all PCa cell lines and not regulated by androgens, and its activity was amplified 97-fold compared to that of a non-amplified promoter. The PEG3AP1-3STA system can thus be used to target advanced AR+ and AR− cells for imaging or immunovirotherapy in advanced PCa.
Highlights
Prostate cancer (PCa) represents the most frequent non-cutaneous malignancy and accounts for a third of all cancer-related deaths in men [1]
While it is clear that some castration-resistant prostate cancer (CRPC) cells can sustain androgen receptor (AR) activity despite low testosterone levels, a number of studies have demonstrated that castration resistance can occur through AR-independent mechanisms [5]
progression elevated gene-3 (PEG3) promoter has been shown to have an essential binding site required for its activity, known as AP1, which is associated with PCa aggressiveness [20]
Summary
Prostate cancer (PCa) represents the most frequent non-cutaneous malignancy and accounts for a third of all cancer-related deaths in men [1]. A non-negligible proportion of men develop recurrence following primary treatment or will present with metastatic disease, rendering them unsuitable candidates for localized therapy [3]. These patients are treated with androgen-deprivation therapy (ADT), which elicits a significant response in the majority of cases [4]. CRPC cells can activate anti-apoptotic pathways that can enable cell survival despite the absence of AR expression [6] Another emerging AR-independent adaptive resistance mechanism is neuroendocrine transdifferentiation [7] through which prostate adenocarcinoma cells undergo a complete phenotypic change to acquire characteristics of small cell carcinoma, thereby giving rise to neuroendocrine prostate cancer (NEPC) [8]. The pathogenesis of castration resistance can be caused by an increase in the number of AR-independent cells, including NEPC cells [9]
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