Prostate cancer (PCa) is one of the most prevalent cancer types in males and the consequences of its distant metastatic deposits are the leading cause of PCa mortality. Therefore, identifying the causes and molecular mechanisms of hematogenous metastasis formation is of considerable clinical importance for the future development of improved therapeutic approaches. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level by targeting messenger RNAs. Numerous studies have identified miRNAs as promotors or inhibitors of metastasis and revealed, in part, their targeting pathways in PCa. Because miRNAs are remarkably stable and can be detected in both tissue and body fluid, its potential as specific biomarkers for metastasis and therapeutic response is also currently under preclinical evaluation. In the present review, we focus on miRNAs that are supposed to initiate or suppress metastasis by targeting several key mRNAs in PCa. Metastasis-suppressing miRNAs include miR-33a-5p, miR-34, miR-132 and miR-212, miR-145, the miR-200 family (incl. miR-141-3p), miR-204-5p, miR-532-3p, miR-335, miR-543, miR-505-3p, miR 19a 3p, miR-802, miR-940, and miR-3622a. Metastasis-promoting RNAs, such as miR-9, miR-181a, miR-210-3, miR-454, miR-671-5p, have been shown to increase the metastatic potential of PCa cells. Other metastasis-related miRNAs with conflicting reports in the literature are also discussed (miR-21 and miR-186). Finally, we summarize the recent developments of miRNA-based therapeutic approaches, as well as current limitations in PCa. Taken together, the metastasis-controlling miRNAs provide the potential to be integrated in the strategy of diagnosis, prognosis, and treatment of metastatic PCa. Nevertheless, there is still a lack of consistency between certain miRNA signatures and reproducibility, which impedes clinical implementation.

Efficacy and mechanism of action of marine alkaloid 3,10-dibromofascaplysin (DBF) were investigated in human prostate cancer (PCa) cells harboring different levels of drug resistance. Anticancer activity was observed across all cell lines examined without signs of cross-resistance to androgen receptor targeting agents (ARTA) or taxane based chemotherapy. Kinome analysis followed by functional investigation identified JNK1/2 to be one of the molecular targets of DBF in 22Rv1 cells. In contrast, no activation of p38 and ERK1/2 MAPKs was observed. Inhibition of the drug-induced JNK1/2 activation or of the basal p38 activity resulted in increased cytotoxicity of DBF, whereas an active ERK1/2 was identified to be important for anticancer activity of the alkaloid. Synergistic effects of DBF were observed in combination with PARP-inhibitor olaparib most likely due to the induction of ROS production by the marine alkaloid. In addition, DBF intensified effects of platinum-based drugs cisplatin and carboplatin, and taxane derivatives docetaxel and cabazitaxel. Finally, DBF inhibited AR-signaling and resensitized AR-V7-positive 22Rv1 prostate cancer cells to enzalutamide, presumably due to AR-V7 down-regulation. These findings propose DBF to be a promising novel drug candidate for the treatment of human PCa regardless of resistance to standard therapy.

(1) Background: The combination of the first-generation antiandrogens and radiotherapy (RT) has been studied extensively in the clinical setting of prostate cancer (PCa). Here, we evaluated the potential radiosensitizing effect of the second-generation antiandrogens abiraterone acetate, apalutamide and enzalutamide. (2) Methods: Cell proliferation and agarose-colony forming assay were used to measure the effect on survival. Double strand break repair efficiency was monitored using immunofluorescence staining of γH2AX/53BP1. (3) Results: We report retrospectively a minor benefit for PCa patients received first-generation androgen blockers and RT compared to patients treated with RT alone. Combining either of the second-generation antiandrogens and 2Gy suppressed cell growth and increased doubling time significantly more than 2Gy alone, in both hormone-responsive LNCaP and castration-resistant C4-2B cells. These findings were recapitulated in resistant sub-clones to (i) hormone ablation (LNCaP-abl), (ii) abiraterone acetate (LNCaP-abi), (iii) apalutamide (LNCaP-ARN509), (iv) enzalutamide (C4-2B-ENZA), and in castration-resistant 22-RV1 cells. This radiosensitization effect was not observable using the first-generation antiandrogen bicalutamide. Inhibition of DNA DSB repair was found to contribute to the radiosensitization effect of second-generation antiandrogens, as demonstrated by a significant increase in residual γH2AX and 53BP1 foci numbers at 24h post-IR. DSB repair inhibition was further demonstrated in 22 patient-derived tumor slice cultures treated with abiraterone acetate before ex-vivo irradiation with 2Gy. (4) Conclusion: Together, these data show that second-generation antiandrogens can enhance radiosensitivity in PCa through DSB repair inhibition, regardless of their hormonal status. Translated into clinical practice, our results may help to find additional strategies to improve the effectiveness of RT in localized PCa, paving the way for a clinical trial.

Significant progress has been achieved in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, results in patients with aggressive variant prostate cancer (AVPC) have been disappointing. Here, we report retrospectively collected data from intensively pretreated AVPC patients (n = 17; 88.2% visceral metastases; 82% elevation of neuroendocrine markers) treated with salvage chemotherapy consisting of cisplatin, ifosfamide, and paclitaxel (TIP). At the interim analysis, 60% of patients showed radiographic response or stable disease (PFS = 2.5 months; OS = 6 months). In men who responded to chemotherapy, an OS > 15 months was observed. Preclinical analyses confirmed the high activity of the TIP regimen, especially in docetaxel-resistant prostate cancer cells. This effect was primarily mediated by increased cisplatin sensitivity in the emergence of taxane resistance. Proteomic and functional analyses identified a lower DNA repair capacity and cell cycle machinery deficiency to be causative. In contrast, paclitaxel showed inconsistent effects, partially antagonizing cisplatin and ifosfamide in some AVPC models. Consequently, paclitaxel has been excluded from the TIP combination for future patients. In summary, we report for the first time the promising efficacy of TIP as salvage therapy in AVPC. Our preclinical data indicate a pivotal role for cisplatin in overcoming docetaxel resistance.

Radiotherapy (RT) is a central treatment for prostate cancer (PCa), relying on the induction of DNA double-strand breaks (DSBs). Tumor ability to repair these breaks limits RT efficacy, making DSB repair inhibitors potential radiosensitizers. However, many of these inhibitors lack tumor specificity and harm normal cells. Therefore, tumor-specific radiosensitization strategies are critically needed for PCa. Approximately 50% of PCa cases harbor the TMPRSS2-ERG gene fusion, leading to overexpression of the ERG transcription factor (ERG ⁺ ). In this study, we demonstrate that ERG ⁺ tumors shift DSB repair toward the poly(ADP-ribose) polymerase 1–dependent end-joining (PARP1-EJ) pathway. Proteomic and Western blot analyses revealed elevated PARP1, XRCC1, and LIG3 levels in ERG ⁺ cells. Notably, PARP inhibition with olaparib increased residual γH2AX/53BP1 foci postirradiation in ERG ⁺ cells, indicating enhanced radiosensitization. In tissue slice cultures (TSCs) from 53 tumors of patients with high-risk PCa, olaparib selectively increased γH2AX/53BP1 foci selectively in ERG ⁺ samples. ERG ⁺ patient–derived organoids also showed significantly delayed growth when treated with olaparib plus RT, compared with either treatment alone. Interestingly, ERG-negative cells within ERG ⁺ TSCs were similarly radiosensitized by olaparib, likely through bystander effect, with residual 53BP1 foci levels comparable to those in ERG ⁺ cells. This was confirmed by medium exchange experiments. These findings suggest that ERG expression promotes dependency on the PARP1-EJ pathway, rendering ERG ⁺ PCa more susceptible to PARP inhibition. This supports combining PARP inhibitors with RT for tumor-selective radiosensitization in ERG ⁺ patients.