Androgen deprivation therapy prevents bladder cancer recurrence Androgen deprivation therapy prevents bladder cancer recurrence

Purpose: Safety and efficacy of acapatamab, a prostate-specific membrane antigen (PSMA) x CD3 bispecific T-cell engager were evaluated in a first-in-human study in metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods: Patients with mCRPC refractory to androgen receptor pathway inhibitor therapy and taxane-based chemotherapy received target acapatamab doses ranging from 0.003 to 0.9 mg in dose exploration (seven dose levels) and 0.3 mg (recommended phase II dose) in dose expansion intravenously every 2 weeks. Safety (primary objective), pharmacokinetics, and antitumor activity (secondary objectives) were assessed. Results: In all, 133 patients (dose exploration, n = 77; dose expansion, n = 56) received acapatamab. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse event seen in 97.4% and 98.2% of patients in dose exploration and dose expansion, respectively; grade ≥ 3 was seen in 23.4% and 16.1%, respectively. Most CRS events were seen in treatment cycle 1; incidence and severity decreased at/beyond cycle 2. In dose expansion, confirmed prostate-specific antigen (PSA) responses (PSA50) were seen in 30.4% of patients and radiographic partial responses in 7.4% (Response Evaluation Criteria in Solid Tumors 1.1). Median PSA progression-free survival (PFS) was 3.3 months [95% confidence interval (CI): 3.0–4.9], radiographic PFS per Prostate Cancer Clinical Trials Working Group 3 was 3.7 months (95% CI: 2.0–5.4). Acapatamab induced T-cell activation and increased cytokine production several-fold within 24 hours of initiation. Treatment-emergent antidrug antibodies were detected in 55% and impacted serum exposures in 36% of patients in dose expansion. Conclusions: Acapatamab was safe and tolerated and had a manageable CRS profile. Preliminary signs of efficacy with limited durable antitumor activity were observed. Acapatamab demonstrated pharmacokinetic and pharmacodynamic activity.

We showed previously that angiotensin II activated the proliferation of prostate cancer cells and that angiotensin II receptor blockers (ARB) could inhibit it. Here, we investigated whether angiotensin II exerts mitogenic effects on the cross-talk between stromal and cancer cells and whether an ARB can inhibit tumor growth through actions on stromal cells. Cell proliferation and interleukin-6 secretion of prostate stromal PrSC cells stimulated with angiotensin II, tumor necrosis factor-α, or epidermal growth factor were examined in the absence and presence of ARB. We examined the effect of ARB on mitogen-activated protein kinase (MAPK) phosphorylation of PrSC and PC-3 cells treated with conditioned medium of PrSC cells and determined the effect of ARB on tumor growth induced by paracrine factors from PrSC cells. Angiotensin II activated the cell proliferation and interleukin-6 secretion of PrSC cells, and ARB inhibited it. Angiotensin II, tumor necrosis factor-α, or epidermal growth factor induced MAPK phosphorylation in PrSC cells, and this phosphorylation was inhibited by ARB. Conditioned medium of PrSC cells with angiotensin II activated MAPK phosphorylation in PC-3 cells, and ARB-treated conditioned medium of PrSC cells inhibited it. The tumor growth and angiogenesis of a mixture of PC-3 with PrSC were inhibited by ARB administration, whereas those of PC-3 xenografts were not inhibited. ARB exerted an antiproliferative effect on prostate cancer through paracrine factors from stromal cells. Because prostate stromal cells are thought to be involved in the initiation and development of prostate cancer, the present data suggest the possibility that ARBs are a novel therapeutic class of agents for prostate cancer.

OBJECTIVE: To determine whether the 2005 International Society of Urologic Pathology (ISUP) Gleason Grading Consensus is clinically more useful than the conventional Gleason score (CGS), we compared the CGS and ISUP GS (IGS) of prostate needle biopsy (NB) and radical prostatectomy (RP) specimens, and evaluated the prognostic value of the ISUP GS. PATIENTS AND METHODS: Of 250 patients undergoing RP, 103 with clinical stage T1–2 N0M0 were enrolled. Pathological tumour grades of NB and RP specimens were classified according to CGS by experienced pathologists in the central pathology department of our hospital, and retrospectively according to IGS by one uropathologist at the central pathology department of another hospital. All patients had RP with no neoadjuvant or adjuvant therapy. We analysed associations of CGS and IGS with biochemical recurrence‐free survival (BRFS) after RP. RESULTS: The concordance rates between NB and RP specimens by CGS and IGS were 64.1% and 69.9%. Under‐grading and over‐grading rates by CGS and IGS were 28.2% and 7.8% for NB, and 27.2% and 2.9% for RP, respectively. There was a significant difference in the over‐grading rate between CGS and IGS ( P = 0.026). When CGS and IGS of NB and RP specimens were compared, the concordance rates were similar, at 67% and 69.9%. The IGS was higher, by 15.6% in NB and by 20.4% in RP specimens, than CGS. Patients were divided into three groups based on IGS of NB specimens (≤6, 7 and ≥8). These groups differed significantly in BRFS after RP ( P = 0.022); CGS showed no such association. CONCLUSIONS: The IGS of NB specimens were significantly associated with BRFS after RP. The ISUP system is thus clinically useful for determining the most appropriate treatments for patients with early‐stage prostate cancer.

Aim:  To clarify the mechanism of the anticancer effect of genistein, we examined the effect of genistein on telomerase activity in prostate cancer cells. We hypothesized that genistein may exert its anticancer effect by modifying telomerase activity in prostate cancer cells.Methods:  Prostate cancer (LNCaP) cells were cultured with genistein and the number of viable cells was counted. Growth medium was also collected to measure prostate‐specific antigen (PSA) concentration. Polymerase chain reaction (PCR)‐based telomeric repeat amplification protocol (TRAP) assay and reverse transcriptase (RT)‐PCR analysis were performed to investigate telomerase activity and the expression of human telomerase reverse transcriptase (hTERT), c‐myc and p21 mRNA. To examine the possibility that hTERT transcriptional activity is modulated by genistein, transient cell transfection studies were performed by using luciferase reporter assay. Telomere repeat amplification protocol (TRAP) assay and PCR analysis of hTERT were performed in androgen independent cells, DU‐145.Results:  Cell growth of LNCaP was inhibited by genistein and PSA secretion was similarly reduced. In TRAP assay, the telomerase activity of LNCaP cells was reduced by genistein. Reverse transcriptase‐PCR analysis revealed that the expression of hTERT and c‐myc mRNA was down‐regulated by genistein, whereas p21 mRNA increased in response to genistein. Luciferase reporter assay revealed that genistein reduced the transcriptional activity of hTERT. In DU‐145 cells, telomerase activity and the expression of hTERT mRNA were also reduced by genistein.Conclusion:  The current study elucidated the molecular mechanism of cell growth inhibition by genistein. The antiproliferative effects of genistein seem to be exerted on the hTERT transcriptional activity via different molecular pathways.

Understanding the mechanism by which hormone refractory prostate cancer (HRPC) develops remains a major issue. Alterations in HRPC include androgen receptor (AR) changes. In addition, the AR is activated by cytokines such as interleukin-6 (IL-6). Atypical protein kinase C (aPKCλ/ι) has been implicated in the progression of several cancers. Herein, we provide evidence that aPKCλ/ι expression correlates with prostate cancer recurrence. Experiments in vitro and in vivo revealed aPKCλ/ι to be involved in prostate cancer cell growth through secretion of IL-6. Further, aPKCλ/ι activates transcription of the IL-6 gene through NFκB and AP-1. We conclude that aPKCλ/ι promotes the growth of hormone independent prostate cancer cells by stimulating IL-6 production in an autocrine manner. Our findings not only explain the link between aPKCλ/ι and IL-6, implicated in the progression a variety of cancers, but also establish a molecular change involved in the development of HRPC. Further, aPKCλ/ι expression might be a biomarker for prostate cancer progression.