Prostate cancer (PCa) is the most common cancer and the 2nd leading cause of cancer-related deaths among men in the United States. Androgen-deprivation-therapy (ADT) with antiandrogens to target the androgens/androgen receptor (AR) signals remains the standard therapy for advanced PCa. However, most of the PCa patients who received ADT with antiandrogens, including the recently developed Enzalutamide (Enz) that might extend PCa patients survival an extra 4.8 months, will still develop the castration (or antiandrogen) resistance. Mechanism dissection studies suggest these antiandrogen resistances may involve the induction of AR splicing variants and/or AR mutants. Further preclinical in vitro/in vivo studies suggest ADT-antiandrogens may also enhance the neuroendocrine differentiation (NED) and PCa cell invasion, and these unwanted side-effects may function through various mechanisms including altering the infiltrating inflammatory cells within the prostate tumor microenvironment. This review summarizes these unwanted ADT-induced side-effects and discusses multiple approaches to overcome these side-effects to better suppress the PCa at the castration resistant stage.

Phosphatase and tensin homolog (PTEN) deficiency is associated with development, progression, and metastasis of various cancers. However, changes in gene expression associated with PTEN deficiency have not been fully characterized. To explore genes with altered expression in PTEN‑deficient cells, the present study generated a PTEN‑knockout cell line (ΔPTEN) from a mouse prostate cancer‑derived cell line using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‑associated protein 9 (CRISPR/Cas9) gene editing system. Following transfection of the CRISPR/Cas9 construct, DNA sequencing was performed to identify deletion of the Pten locus and PTEN inactivation was verified by western blotting. The ΔPTEN cell line exhibited enhanced RAC‑alpha serine/threonine‑protein kinase phosphorylation and cyclin D1 expression. In addition, an increase in cell proliferation and colony formation was observed in the ΔPTEN cell line. Gene expression profiling experiments were analyzed with microarray and microRNA (miRNA) arrays. In the microarray analysis, 111 genes exhibited ≥10‑fold increased expression compared with the parent strain and mock cell line and 23 genes were downregulated. The only miRNA with increased expression of 10‑fold or more was mmu‑miR‑210‑3p. Genes with enhanced expression included genes involved in the development, progression, and metastasis of cancer such as Tet methylcytosine dioxygenase 1, twist family BHLH transcription factor 2, C‑fos‑induced growth factor and Wingless‑Type MMTV Integration Site Family, Member 3, and genes involved in immunosuppression such as Arginase 1. The results of the present study suggest that PTEN deficiency mobilizes a variety of genes critical for cancer cell survival and host immune evasion.

Despite the availability of a number of treatment options, certain cases of primary prostate cancer (PCa) will develop into metastatic PCa, in which epithelial‑mesenchymal transition (EMT) serves an important role. Recently, a natural flavonoid known as 2'‑hydroxyflavanone (2HF) exerts remarkable anticancer activity on various types of cancer. Our previous study demonstrated that 2HF could promote apoptosis and inhibit the proliferation of PCa cells, but whether 2HF is involved in the regulation of EMT, and cell migration and invasion in metastatic PCa remains unknown. The present study used two different metastatic PCa cell lines (PC‑3 and DU145) to investigate the effects of 2HF on EMT, and cell migration and invasion. The results demonstrated that 2HF could inhibit EMT, and cell migration and invasion through the Wnt/β‑catenin signaling pathway by suppressing GSK‑3β phosphorylation, β‑catenin expression and transactivation. In conclusion, the present study revealed a novel function of 2HF, which may be used to prevent or treat PCa metastasis.

As the crucial issue in the development of anti‑angiogenic drugs is how to predict which patients will and will not benefit prior to the initiation of therapy, angiogenic 18F‑alfatide positron emission computed tomography (PET) was assessed in the present study. Lung adenocarcinoma A549 (high angiogenesis) and prostate PC‑3 (low angiogenesis) cell xenografted tumor‑bearing mice underwent 18F‑alfatide PET at baseline and following treatment with either an anti‑angiogenic therapy or vehicle. The evaluation index for the inhibition of tumor growth in the individuals in the treated groups was represented by treatment/control (T/C) ratio (%). Anti‑angiogenic responses were denoted by the changes in 18F‑alfatide uptake in the same animal. The T/C ratio was lower in high‑uptake tumors than in low‑uptake tumors (P=0.001). A significant difference in the tumor volumes between the anti‑angiogenic therapy group and the control group occurred earlier in the A549 model than in the PC‑3 model. 18F‑alfatide uptake decreased more for A549 tumors than for PC‑3 tumors following anti‑angiogenic therapy. In each treatment group, the degree of tumor response to anti‑angiogenic therapy was associated well with the tumor uptake prior to treatment (P<0.05). These results indicated that 18F‑alfatide PET may be a useful molecular imaging tool for individual selection prior to anti‑angiogenic drug therapy.

Isothiocyanates (ITCs) have gained increasing attention since they have been attributed the merits for the potential beneficial effects of cruciferous vegetable dietary consumption on cancer. The aim of the present study was to determine the cytotoxic effects of 3-butenyl ITC (3-BI) on prostate cancer (PC) cells under in vitro conditions. Two androgen-insensitive human PC cell lines, PC-3 and DU145, were assayed. Cells were cultured in the presence of increasing concentrations of 3-BI (5, 10, 30 and 50 µM) in the absence or presence of the chemotherapeutic drug docetaxel (DOCE) (1 and 2 nM). The cytotoxic effects of these compounds were analyzed using the trypan blue exclusion assay at 24, 48 and 72 h. Apoptosis and migration assays were also performed. The results showed that 3-BI induced a dose-dependent cytotoxic effect on PC-3 cells at 24, 48 and 72 h. These effects were significantly higher than those found with DOCE at 72 h of culture. Moreover, 3-BI also potentiated the effects of DOCE in a dose-dependent manner. Additionally, 3-BI showed inhibition of the migration of PC-3 cells. Nevertheless, 3-BI was not effective in the DU145 PC cell line. These results show a promising role for the 3-BI compound as a co-adjuvant agent in DOCE-based therapy in certain types of PC.

Prostate cancer (PC) is the most common type of cancer among men. Aggressive and metastatic PC results in life-threatening tumors, and represents one of the leading causes of mortality in men. Previous studies of atypical protein kinase C isoforms (aPKCs) have highlighted its role in the survival of cultured prostate cells via the nuclear factor (NF)-κB pathway. The present study showed that PKC‑ι was overexpressed in PC samples collected from cancer patients but not in non-invasive prostate tissues, indicating PKC‑ι as a possible prognostic biomarker for the progression of prostate carcinogenesis. Immunohistochemical staining further confirmed the association between PKC‑ι and the prostate malignancy. The DU‑145 and PC‑3 PC cell lines, and the non-neoplastic RWPE‑1 prostatic epithelial cell line were cultured and treated with aPKC inhibitors 2‑acetyl‑1,3-cyclopentanedione (ACPD) and 5-amino‑1-(1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)‑1H-imidazole-4-carboxamide (ICA‑1). Western blot data demonstrated that ICA‑1 was an effective and specific inhibitor of PKC‑ι and that ACPD inhibited PKC‑ι and PKC‑ζ. Furthermore, the two inhibitors significantly decreased malignant cell proliferation and induced apoptosis. The inhibitors showed no significant cytotoxicity towards the RWPE‑1 cells, but exhibited cytostatic effects on the DU‑145 and PC‑3 cells prior to inducing apoptosis. The inhibition of aPKCs significantly reduced the translocation of NF-κB to the nucleus. Furthermore, this inhibition promoted apoptosis, reduced signaling for cell survival, and reduced the proliferation of PC cells, whereas the normal prostate epithelial cells were relatively unaffected. Overall, the results suggested that PKC‑ι and PKC‑ζ are essential for the progression of PC, and that ACPD and ICA‑1 can be effectively used as potential inhibitors in targeted therapy.

High dose rate (HDR) brachytherapy planning usually involves an iterative process of refining planning objectives until a clinically acceptable plan is produced. The purpose of this two-part study is to improve current planning practice by designing a novel inverse planning algorithm based on multi-criteria optimization (MCO). In the first part, complete Pareto surfaces were approximated and studied for prostate cases.&#13; &#13; A Pareto surface approximation algorithm was implemented within the framework of Inverse Planning Simulated Annealing (IPSA). The Pareto surfaces of 140 prostate cases were approximated with the proposed MCO algorithm. For each case, the Pareto surface was represented by automatically generating 300 Pareto optimal plans, and the clinically acceptable region was identified. Thus, 42000 Pareto optimal plans were created to characterize Pareto surfaces for all the cases. In addition, the relationship between the clinically acceptable region and 4 anchor plans was studied. As a result, a set of polynomial regression models was extracted to rapidly predict the clinically acceptable region on the Pareto surface based on anchor plans.&#13; &#13; Pareto surfaces for HDR brachytherapy prostate cases were well characterized in this study. The proposed regression models may help define the most relevant solution phase space.

The current iterative approach to inverse planning of high dose rate (HDR) treatment planning can be time consuming. The purpose of this two-part study is to streamline the planning process while maintaining plan quality. In this second part, a multi-criteria optimization (MCO) planning algorithm is proposed and benchmarked against a standard planning algorithm.&#13; With a set of previously established regression models, a patient-specific valid solution space on the Pareto surface was predicted based on the anchor plans results. Alternative plans generated alongside the partial Pareto front were presented to the planner, and one plan was selected as the MCO plan. The dosimetric parameters results as well as the planning time were compared between the MCO plans and the physician-approved standard plans for 236 prostate cases.&#13; Results show that the urethra is better spared with MCO planning than with standard planning (a lower mean urethral D10 value of 2.25%). The overall plan MCO quality also outperforms the standard plan quality, since MCO planning is able to increase the frequency of clinically acceptable plans meeting all of RTOG criteria simultaneously without any human intervention (from 83.05 % to 97.46 %). Finally, the average MCO planning time is 41 s without any interventions of treatment planners.&#13; The presented MCO planning algorithm constitutes a robust and automated way to improve treatment quality in brachytherapy.

Purpose To compare the diagnostic accuracy of gallium 68 (68Ga)-labeled prostate-specific membrane antigen (PSMA)-11 PET/MRI with that of multiparametric MRI in the detection of prostate cancer. Materials and Methods The authors performed a retrospective study of men with biopsy-proven prostate cancer who underwent simultaneous 68Ga-PSMA-11 PET/MRI before radical prostatectomy between December 2015 and June 2017. The reference standard was whole-mount pathologic examination. Readers were blinded to radiologic and pathologic findings. Tumor localization was based on 30 anatomic regions. Region-specific sensitivity and specificity were calculated for PET/MRI and multiparametric MRI by using raw stringent and alternative neighboring approaches. Maximum standardized uptake value (SUVmax) in the tumor and Prostate Imaging Reporting and Data System (PI-RADS) version 2 grade were compared with tumor Gleason score. Generalized estimating equations were used to estimate population-averaged sensitivity and specificity and to determine the association between tumor characteristics and SUVmax or PI-RADS score. Results Thirty-two men (median age, 68 years; interquartile range: 62-71 years) were imaged. The region-specific sensitivities of PET/MRI and multiparametric MRI were 74% (95% confidence interval [CI]: 70%, 77%) and 50% (95% CI: 45%, 0.54%), respectively, with the alternative neighboring approach (P < .001 for both) and 73% (95% CI: 68%, 79%) and 69% (95% CI: 62%, 75%), respectively, with the population-averaged generalized estimating equation (P = .04). Region-specific specificity of PET/MRI was similar to that of multiparametric MRI with the alternative neighboring approach (88% [95% CI: 85%, 91%] vs 90% [95% CI: 87%, 92%], P = .99) and in population-averaged estimates (70% [95% CI: 64%, 76%] vs 70% [95% CI: 64%, 75%], P = .99). SUVmax was associated with a Gleason score of 7 and higher (odds ratio: 1.71 [95% CI: 1.27, 2.31], P < .001). Conclusion The sensitivity of gallium 68-labeled prostate-specific membrane antigen-11 PET/MRI in the detection of prostate cancer is better than that of multiparametric MRI. © RSNA, 2018 See also the editorial by Civelek in this issue.