Apalutamide versus bicalutamide in combination with androgen deprivation therapy for metastatic hormone sensitive prostate cancer.

The objective of this study is to compare the efficacy of apalutamide and bicalutamide in combination with androgen deprivation therapy in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We retrospectively collected the data of about 330 patients with metastatic hormone-sensitive prostate cancer at our hospital and affiliated hospitals between December 2013 and August 2023. Sixty-one patients were administered apalutamide (240 mg/day) with androgen deprivation therapy (group A), and 269 patients were administered bicalutamide (80 mg/day) with androgen deprivation therapy (group B). Propensity score matching was used to adjust for clinical background factors between the two groups. PSA progression-free survival and overall survival were significantly longer in group A than in group B among the matched patients. Apalutamide therapy was a significant independent factor for OS in matched patients. The second progression-free survival of group A was significantly longer than that of group B in matched patients. Patients treated with apalutamide achieved ≥ 90% PSA decline from baseline faster and in larger numbers than those with bicalutamide. Apalutamide combined with ADT may be superior to bicalutamide alone in terms of OS and PSA-PFS in patients with mHSPC.

Predictive factors for the efficacy of abiraterone acetate therapy in high-risk metastatic hormone-sensitive prostate cancer patients.

PURPOSE: There is a discrepancy in the efficacy of abiraterone acetate for overall survival (OS) in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). This study aimed to identify predictive factors for the efficacy of abiraterone acetate for OS in high-risk mHSPC patients by analyzing them over a longer observation period. METHODS: Five hundred high-risk mHSPC patients were retrospectively identified at our hospital and affiliated hospitals in the Kindai Oncology Study Group and Kyoto Prefectural University of Medicine Oncology Study Group between December 2013 and March 2022. Two hundred patients were treated with abiraterone acetate (1000 mg/day) plus prednisolone (5 mg/day) combined with androgen deprivation therapy (ADT). A total of 300 patients were treated with bicalutamide (80 mg/day) in combination with ADT. RESULTS: OS was not significantly different between the two treatments in the overall cohort (p = 0.1643). In the subgroup without Gleason pattern 5 at the primary lesion, OS was significantly better in patients treated with abiraterone acetate than in those treated with bicalutamide (p = 0.0192). In the subgroup with Gleason pattern 5 at the primary lesion, no significant difference was found between the two treatments (p = 0.1799). Univariate and multivariate analyses in the subgroup without Gleason pattern 5 at the primary lesion suggested that abiraterone therapy may be an important and independent predictor of OS in high-risk mHSPC patients. CONCLUSION: The presence of Gleason pattern 5 at the primary lesion may be a predictor for high-risk mHSPC patients who could benefit from abiraterone acetate treatment.

MRGBP promotes AR-mediated transactivation of KLK3 and TMPRSS2 via acetylation of histone H2A.Z in prostate cancer cells.

The androgen receptor (AR) promotes growth of prostate cancer cells by controlling the expression of target genes. This study showed that MRG domain binding protein (MRGBP) accelerated AR-mediated transactivation. We first showed that MRGBP promoted growth of AR-positive prostate cancer cells. MRGBP increased the expression of certain AR target genes, including KLK3 and TMPRSS2, and it associated with AR binding regions of these genes during androgen treatment. Furthermore, MRGBP interacted with MRG15 and TIP60 in prostate cancer cells. Androgen-stimulated AR enhanced histone H3K4me1 or H3K4me3 levels at AR binding regions. MRGBP was recruited to active gene regions through its binding with H3K4me1/3 by MRG15. Then, MRGBP promoted recruitment of TIP60 and acetylation of histone variant H2A.Z at the location of AR binding. Accordingly, AR occupancy of the AR binding regions was increased by MRGBP. Together, these results suggest that MRGBP promotes activation of AR-associated enhancer and promoter regions through an epigenetic mechanism.

CNPY2 inhibits MYLIP-mediated AR protein degradation in prostate cancer cells.

The androgen receptor (AR) is a ligand-dependent transcription factor that promotes prostate cancer (PC) cell growth through control of target gene expression. This report suggests that Canopy FGF signaling regulator 2 (CNPY2) controls AR protein levels in PC cells. We found that AR was ubiquitinated by an E3 ubiquitin ligase, myosin regulatory light chain interacting protein (MYLIP) and then degraded through the ubiquitin-proteasome pathway. CNPY2 decreased the ubiquitination activity of MYLIP by inhibition of interaction between MYLIP and UBE2D1, an E2 ubiquitin ligase. CNPY2 up-regulated gene expression of AR target genes such as KLK3 gene which encodes the prostate specific antigen (PSA) and promoted cell growth of PC cells. The cell growth inhibition by CNPY2 knockdown was rescued by AR overexpression. Furthermore, positive correlation of expression levels between CNPY2 and AR/AR target genes was observed in tissue samples from human prostate cancer patients. Together, these results suggested that CNPY2 promoted cell growth of PC cells by inhibition of AR protein degradation through MYLIP-mediated AR ubiquitination.

CNPY2 promoted the proliferation of renal cell carcinoma cells and increased the expression of TP53.

Renal cell carcinoma (RCC) is the most common type of kidney cancer. However, the mechanisms underlying the progression of the disease are not well understood. The data in this report suggest that canopy FGF signaling regulator 2 (CNPY2) is a promoter of RCC progression. We found that CNPY2 significantly promoted growth of RCC cells and upregulated TP53 gene expression. Although TP53 is widely known as a tumor suppressor, in RCC TP53 promoted tumor cell growth. A typical p53 target gene, CDKN1A, was upregulated by both p53 and CNPY2 in RCC cells, suggesting that CNPY2 increased the expression level of TP53. Consistent with these results, CNPY2 and TP53 expression levels were positively correlated in RCC patients. These findings suggested that CNPY2 promoted cancer cell growth in RCC through regulating TP53 gene expression.

Androgen suppresses testicular cancer cell growth in vitro and in vivo.

Silencing of androgen receptor (AR)-meditated androgen signaling is thought to be associated with the development of testicular germ cell tumors (TGCTs). However, the role of the androgen/AR signal in TGCT development has not been investigated. In this study, we show that the androgen/AR signal suppressed the cell growth of seminomas (SEs), a type of TGCT, in vitro and in vivo. Growth of SE cells was suppressed by DHT treatment and reduction of androgen levels by surgical castration promoted cancer cell growth in an in vivo xenograft model. Tryptophan hydroxylase 1 (TPH1), the rate limit enzyme in serotonin synthesis, was one of the genes which expression was reduced in DHT-treated SE cells. TPH1 was highly expressed in SE cancer tissues compared with adjacent normal tissues. Activation of androgen/AR signaling in SE cells reduced the expression of TPH1 in SE cells, followed by the reduction of serotonin secretion in cell culture supernatant. These results suggested that silencing of androgen/AR signaling may cause initiation and progression of SE through increase in TPH1 gene expression level.

PAX2 promoted prostate cancer cell invasion through transcriptional regulation of HGF in an in vitro model.

Elucidating the mechanism of prostate cancer cell invasion may lead to the identification of novel therapeutic strategies for its treatment. Paired box 2 (PAX2) and hepatocyte growth factor (HGF) proteins are promoters of prostate cancer cell invasion. We found that PAX2 protein activated the HGF gene promoter through histone H3 acetylation and upregulated HGF gene expression. Deletion analysis revealed that the region from -637 to -314 of the HGF gene was indispensable for HGF promoter activation by PAX2. This region contains consensus PAX2 binding sequences and mutations of the sequences attenuated HGF promoter activation. Using an in vitro invasion model, we found that PAX2 and HGF promoted prostate cancer cell invasion in the same pathway. Knockdown of HGF expression attenuated the cells' invasive capacity. Moreover, in tissue samples of human prostate cancers, HGF and PAX2 expression levels were positively correlated. These results suggested that upregulation of HGF gene expression by PAX2 enhanced the invasive properties of prostate cancer cells. The PAX2/HGF pathway in prostate cancer cells may be a novel therapeutic target in prostate cancer patients.

A genetic screen in Drosophila for regulators of human prostate cancer progression.

To uncover the mechanism by which human prostate cancer progresses, we performed a genetic screen for regulators of human prostate cancer progression using the Drosophila accessory gland, a functional homolog of the mammalian prostate. Cell growth and migration of secondary cells in the adult male accessory gland were found to be regulated by paired, N-cadherin, and E-cadherin, which are Drosophila homologues of regulators of human prostate cancer progression. Using this screening system, we also identified three genes that promoted growth and migration of secondary cells in the accessory gland. The human homologues of these candidate genes - MRGBP, CNPY2, and MEP1A - were found to be expressed in human prostate cancer model cells and to promote replication and invasiveness in these cells. These findings suggest that the development of the Drosophila accessory gland and human prostate cancer cell growth and invasion are partly regulated through a common mechanism. The screening system using the Drosophila accessory gland can be a useful tool for uncovering the mechanisms of human prostate cancer progression.