Tanshinone analog inhibits castration-resistant prostate cancer cell growth by inhibiting glycolysis in an AR-dependent manner.

Androgen receptor (AR) is one of the key targets for the treatment of castration-resistant prostate cancer (CRPC). Current endocrine therapy can greatly improve patients with CRPC. However, with the change of pathogenic mechanism, acquired resistance often leads to the failure of treatment. Studies have shown that tanshinone IIA (TS-IIA) and its derivatives have significant antitumor activity, and have certain AR-targeting effects, but the mechanism is unknown. In this study, the TS-IIA analog TB3 was found to significantly inhibit the growth of CRPC in vitro and in vivo. Molecular docking, cellular thermal shift assay, and cycloheximide experiments confirmed that AR was the target of TB3 and promoted the degradation of AR. Furthermore, TB3 can significantly inhibit glycolysis metabolism by targeting the AR/PKM2 axis. The addition of pyruvic acid could significantly alleviate the inhibitory effect of TB3 on CRPC cells. Besides, the knockdown of AR or PKM2 also could reverse the effect of TB3 on CRPC cells. Taken together, our study suggests that TS-IIA derivative TB3 inhibits glycolysis to prevent the CRPC process by targeting the AR/PKM2 axis.

The correlation between TRIM28 expression and immune checkpoints in CRPC.

This study delves into the unexplored realm of castration-resistant prostate cancer (CRPC) by investigating the role of TRIM28 and its intricate molecular mechanisms using high-throughput single-cell transcriptome sequencing and advanced bioinformatics analysis. Our comprehensive examination unveiled dynamic TRIM28 expression changes, particularly in immune cells such as macrophages and CD8+ T cells within CRPC. Correlation analyses with TCGA data highlighted the connection between TRIM28 and immune checkpoint expression and emphasized its pivotal influence on the quantity and functionality of immune cells. Using TRIM28 knockout mouse models, we identified differentially expressed genes and enriched pathways, unraveling the potential regulatory involvement of TRIM28 in the cGAS-STING pathway. In vitro, experiments further illuminated that TRIM28 knockout in prostate cancer cells induced a notable anti-tumor immune effect by inhibiting M2 macrophage polarization and enhancing CD8+ T cell activity. This impactful discovery was validated in an in situ transplant tumor model, where TRIM28 knockout exhibited a deceleration in tumor growth, reduced proportions of M2 macrophages, and enhanced infiltration of CD8+ T cells. In summary, this study elucidates the hitherto unknown anti-tumor immune role of TRIM28 in CRPC and unravels its potential regulatory mechanism via the cGAS-STING signaling pathway. These findings provide novel insights into the immune landscape of CRPC, offering promising directions for developing innovative therapeutic strategies.

Characterization of HOXB13 expression patterns in localized and metastatic castration-resistant prostate cancer.

HOXB13 is a key lineage homeobox transcription factor that plays a critical role in the differentiation of the prostate gland. Several studies have suggested that HOXB13 alterations may be involved in prostate cancer development and progression. Despite its potential biological relevance, little is known about the expression of HOXB13 across the disease spectrum of prostate cancer. To this end, we validated a HOXB13 antibody using genetic controls and investigated HOXB13 protein expression in murine and human developing prostates, localized prostate cancers, and metastatic castration-resistant prostate cancers. We observed that HOXB13 expression increases during later stages of murine prostate development. All localized prostate cancers showed HOXB13 protein expression. Interestingly, lower HOXB13 expression levels were observed in higher-grade tumors, although no significant association between HOXB13 expression and recurrence or disease-specific survival was found. In advanced metastatic prostate cancers, HOXB13 expression was retained in the majority of tumors. While we observed lower levels of HOXB13 protein and mRNA levels in tumors with evidence of lineage plasticity, 84% of androgen receptor-negative castration-resistant prostate cancers and neuroendocrine prostate cancers (NEPCs) retained detectable levels of HOXB13. Notably, the reduced expression observed in NEPCs was associated with a gain of HOXB13 gene body CpG methylation. In comparison to the commonly used prostate lineage marker NKX3.1, HOXB13 showed greater sensitivity in detecting advanced metastatic prostate cancers. Additionally, in a cohort of 837 patients, 383 with prostatic and 454 with non-prostatic tumors, we found that HOXB13 immunohistochemistry had a 97% sensitivity and 99% specificity for prostatic origin. Taken together, our studies provide valuable insight into the expression pattern of HOXB13 during prostate development and cancer progression. Furthermore, our findings support the utility of HOXB13 as a diagnostic biomarker for prostate cancer, particularly to confirm the prostatic origin of advanced metastatic castration-resistant tumors. © 2023 The Pathological Society of Great Britain and Ireland.

AR-V7 expression facilitates accelerated G2/M phase transition in castration-resistant prostate cancer.

The emergence of AR-V7, a truncated isoform of AR upon androgen deprivation therapy treatment, leads to the development of castration resistant prostate cancer (CRPC). Understanding mechanisms that regulate AR-V7 expression is critical for developing newer therapeutic strategies. In this study, we have investigated the regulation of AR-V7 during cell cycle and identified a distinct pattern of periodic fluctuation, peaking during G2/M phase. This fluctuation correlates with the expression of Cdc-2 like kinase 1 (CLK1) and phosphorylated serine/arginine-rich splicing factor 1 (p-SRSF1) during these phases, pointing towards their role in AR-V7 generation. Functional assays reveal that CLK1 knockdown prolongs the S phase, leading to altered cell cycle distribution and increased accumulation of AR-V7 and pSRSF1 in G1/S phase. Conversely, CLK1 overexpression rescues AR-V7 and p-SRSF1 levels in the G2/M phase, consistent with observed cell cycle alterations upon AR-V7 knockdown and overexpression in CRPC cells. Furthermore, overexpression of kinase-deficient CLK1 mutant leads to diminished AR-V7 levels during G2/M, underlining the essential contribution of CLK1's kinase activity in modulating AR-V7 expression. Collectively, our findings, for the first time, show periodic regulation of AR-V7 expression, its effect on cell cycle progression and the critical role of CLK1-pSRSF1 axis in modulating AR-V7 expression throughout the cell cycle.

Real-world safety and effectiveness of radium-223 in patients with metastatic castration-resistant prostate cancer: Interim analyses of the prospective, observational RAPIT study.

Several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC) are available, including radium-223 dichloride (223Ra), which was approved based on phase 3 data demonstrating improved overall survival (OS) and a favorable safety profile. To date, real-world evidence for 223Ra use in Taiwan is from three studies of <50 patients. This observational study (NCT04232761) enrolled male patients with histologically/cytologically confirmed mCRPC with bone metastases from centers across Taiwan. 223Ra was prescribed as part of routine practice by investigators. Patients with prior 223Ra treatment were excluded. The primary objective was to assess 223Ra safety; secondary objectives evaluated efficacy parameters, including OS. Overall, 224 patients were enrolled. Most patients had an Eastern Cooperative Oncology Group performance status of 0/1 (79.0%) and ≤20 bone metastases (69.2%); no patients had visceral metastases. 223Ra was first- or second-line therapy in 23.2% and 47.7% of patients, respectively. The total proportion of patients who received 5-6 223Ra cycles was 68.8%; this proportion was greater with first-line use (84.3%) than second- (65.7%) or third-/fourth-line use (64.1%). More chemotherapy-naïve patients (61.9%) completed the 6-cycle 223Ra treatment than chemotherapy-exposed patients (56.7%). Any-grade treatment-emergent adverse events (TEAEs) and serious TEAEs occurred in 54.0% and 28.6% of patients, respectively, while 12% experienced 223Ra-related adverse events. Median OS was 15.7 months (95% confidence interval 12.13-19.51); patients receiving 5-6 223Ra injections and earlier 223Ra use had longer OS than those receiving fewer injections and later 223Ra use. 223Ra provides a well-tolerated and effective treatment for Taiwanese patients with mCRPC and bone metastases.

Clinical validation of circulating GDF15/MIC-1 as a marker of response to docetaxel and survival in men with metastatic castration-resistant prostate cancer.

BACKGROUND: Elevated circulating growth differentiation factor (GDF15/MIC-1), interleukin 4 (IL4), and IL6 levels were associated with resistance to docetaxel in an exploratory cohort of men with metastatic castration-resistant prostate cancer (mCRPC). This study aimed to establish level 2 evidence of cytokine biomarker utility in mCRPC. METHODS: IntVal: Plasma samples at baseline (BL) and Day 21 docetaxel (n = 120). ExtVal: Serum samples at BL and Day 42 of docetaxel (n = 430). IL4, IL6, and GDF15 levels were measured by ELISA. Monocytes and dendritic cells were treated with 10% plasma from men with high or low GDF15 or recombinant GDF15. RESULTS: IntVal: Higher GDF15 levels at BL and Day 21 were associated with shorter overall survival (OS) (BL; p = 0.03 and Day 21; p = 0.004). IL4 and IL6 were not associated with outcomes. ExtVal: Higher GDF15 levels at BL and Day 42 predicted shorter OS (BL; p < 0.0001 and Day 42; p < 0.0001). Plasma from men with high GDF15 caused an increase in CD86 expression on monocytes (p = 0.03), but was not replicated by recombinant GDF15. CONCLUSIONS: Elevated circulating GDF15 is associated with poor prognosis in men with mCRPC receiving docetaxel and may be a marker of changes in the innate immune system in response to docetaxel resistance. These findings provide a strong rationale to consider GDF15 as a biomarker to guide a therapeutic trial of drugs targeting the innate immune system in combination with docetaxel in mCRPC.

A novel HDAC6 inhibitor interferes microtubule dynamics and spindle assembly checkpoint and sensitizes cisplatin-induced apoptosis in castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (CRPC), the most refractory prostate cancer, inevitably progresses and becomes unresponsive to hormone therapy, revealing a pressing unmet need for this disease. Novel agents targeting HDAC6 and microtubule dynamics can be a potential anti-CRPC strategy. METHODS: Cell proliferation was examined in CRPC PC-3 and DU-145 cells using sulforhodamine B assay and anchorage-dependent colony formation assay. Flow cytometric analysis of propidium iodide staining was used to determine cell-cycle progression. Cell-based tubulin polymerization assay and confocal immunofluorescence microscopic examination determine microtubule assembly/disassembly status. Protein expressions were determined using Western blot analysis. RESULTS: A total of 82 novel derivatives targeting HDAC6 were designed and synthesized, and Compound 25202 stood out, showing the highest efficacy in blocking HDAC6 (IC50, 3.5 nM in enzyme assay; IC50, 1.0 µM in antiproliferative assay in CRPC cells), superior to tubastatin A (IC50, 5.4 µM in antiproliferative assay). The selectivity and superiority of 25202 were validated by examining the acetylation of both α-tubulin and histone H3, detecting cell apoptosis and HDACs enzyme activity assessment. Notably, 25202 but not tubastatin A significantly decreased HDAC6 protein expression. 25202 prolonged mitotic arrest through the detection of cyclin B1 upregulation, Cdk1 activation, mitotic phosphoprotein levels, and Bcl-2 phosphorylation. Compound 25202 did not mimic docetaxel in inducing tubulin polymerization but disrupted microtubule organization. Compound 25202 also increased the phosphorylation of CDC20, BUB1, and BUBR1, indicating the activation of the spindle assembly checkpoint (SAC). Moreover, 25202 profoundly sensitized cisplatin-induced cell death through impairment of cisplatin-evoked DNA damage response and DNA repair in both ATR-Chk1 and ATM-Chk2 pathways. CONCLUSION: The data suggest that 25202 is a novel selective and potent HDAC6 inhibitor. Compound 25202 blocks HDAC6 activity and interferes microtubule dynamics, leading to SAC activation and mitotic arrest prolongation that eventually cause apoptosis of CRPC cells. Furthermore, 25202 sensitizes cisplatin-induced cell apoptosis through impeding DNA damage repair pathways.

Bellmunt risk score as a survival predictor in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: The prognosis of metastatic castration-resistant prostate cancer (mCRPC) is influenced by numerous individual factors. Despite various proposed prognostic models, the clinical application of these remains limited, probably due to complexity. Our study aimed to evaluate the predictive value of the Bellmunt risk score, which is well-known for urothelial carcinoma and easily assessed, in mCRPC patients. METHODS: The Bellmunt risk score was calculated from three risk factors (Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥1, serum hemoglobin <10 g/dL, presence of liver metastases) in 125 patients who received first-line mCRPC treatment between 2005 and 2023. In addition, a modified score was established (one point each for hemoglobin <10 g/dL and the presence of liver metastases added to the ECOG PS). Associations with overall survival (OS) under first- and second-line therapy were tested using Cox regression analyzes, log-rank tests, concordance index (C-index) and time-dependent receiver operating characteristic. RESULTS: There is a significant correlation between the level of the Bellmunt risk score and shorter OS (hazard ratio: 3.23, 95% confidence interval: 2.06-5.05; log-rank p < 0.001; C-index: 0.724). The semi-quantitative modified risk score showed even better prognostic discrimination (log-rank p < 0.001, C-index: 0.764). The score and its dynamics were also predictive in the second-line setting (log-rank p < 0.001 and = 0.01; C-index: 0.742 and 0.595). CONCLUSIONS: The Bellmunt risk score is easy to assess and provides useful prognostic information in mCRPC, and can support physicians in their treatment decisions.

Impact of proton pump inhibitors on the efficacy of androgen receptor signaling inhibitors in metastatic castration-resistant prostate cancer patients.

BACKGROUND: Proton pump inhibitors (PPIs) are widely used due to their affordability and minimal severe side effects. However, their influence on the efficacy of cancer treatments, particularly androgen receptor signaling inhibitors (ARSIs), remains unclear. This study investigates the impact of PPI usage on the treatment outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: A total of 117 mCRPC patients were retrospectively analyzed and divided into two groups based on the concomitant use of PPI at the initiation of ARSI treatment: PPI+ (n = 38) and PPI- (n = 79). Patient characteristics, including age at ARSI treatment administered, prostate-specific antigen (PSA) value at ARSI treatment administered, International Society of Urological Pathology grade group at prostate biopsy, metastatic site at ARSI treatment administered, prior docetaxel (DTX) treatment, and type of ARSI (abiraterone acetate or enzalutamide) were recorded. Progression-free survival (PFS), overall survival (OS), and PSA response rates were compared between the two groups. Patients were further stratified by clinical background to compare PFS and OS between the two groups. RESULTS: The PPI- group exhibited significantly extended PFS and a trend toward improved OS. For PSA response (reduction of 50% or more from baseline), the rates were 62.3% and 45.9% in the PPI- group and the PPI+ group, respectively. For deep PSA response (reductions of 90% or more from baseline), the rates were 36.4% and 24.3% in the PPI- group and the PPI+ group, respectively. The effects were consistent across subgroups divided by prior DTX treatment and type of ARSI administered. CONCLUSIONS: The administration of PPIs appears to diminish the therapeutic efficacy of ARSIs in mCRPC patients. Further prospective studies are needed to confirm these findings and explore the biological mechanisms involved.

CD44 and CD133 protein expression might serve as a prognostic factor for early occurrence castration-resistant prostate cancer.

BACKGROUND: The occurrence of castration-resistant prostate cancer (CRPC) varies in patients with advanced prostate cancer (PCa) undergoing androgen deprivation therapy (ADT). The rate of occurrence of CRPC may be related to the presence of prostate cancer stem cells (CSC). Thus, this study aims to evaluate the presence of CSC markers (CD44 and CD133) in histopathology tissue at the time of diagnosis and their correlation with the occurrence of CRPC in patients with advanced PCa within 2 years of ADT. METHOD: A retrospective case-control study was conducted to evaluate the incidence of CRPC within 2 years. The inclusion criteria were patients with PCa who had received treatment with ADT and a first-generation anti-androgen (AA) for 2 years. We classified patients based on whether they developed CRPC within 2 years (CRPC) of the therapy or did not experience CRPC within 2 years (non-CRPC) of the therapy. We performed immunohistochemical (IHC) staining for CD44 and CD133 on the prostate biopsy tissue samples. RESULTS: Data were collected from records spanning 2011-2019. We analyzed a total of 65 samples, including 22 patients with CRPC and 43 patients with non-CRPC who had received treatment with LHRH agonists and AA for up to 2 years. Our findings showed a significant H-score difference in CD44 protein expression between CRPC prostate adenocarcinoma samples 869 (200-1329) and non-CRPC 524 (154-1166) (p = 0.033). There was no significant difference in CD133 protein expression between the two groups (p = 0.554). However, there was a significant difference in the nonoccurrence of CRPC between the high expressions of both CD44 and CD133 groups with other expressions of CD44/CD133 groups (25% vs. 75%; p = 0.011; odds ratio = 4.29; 95% confidence interval [1.34, 13.76]). CONCLUSION: This study found a low expression of at least one CD44/CD133 protein in the patients without early occurrence of CRPC. This result might suggest that CD44/CD133 may function as a potential prognostic marker for PCa, especially in a low expression, to identify patients who have a better prognosis regarding the occurrence of early CRPC.

L1CAM mediates neuroendocrine phenotype acquisition in prostate cancer cells.

BACKGROUND: A specific type of prostate cancer (PC) that exhibits neuroendocrine (NE) differentiation is known as NEPC. NEPC has little to no response to androgen deprivation therapy and is associated with the development of metastatic castration-resistant PC (CRPC), which has an extremely poor prognosis. Our understanding of genetic drivers and activated pathways in NEPC is limited, which hinders precision medicine approaches. L1 cell adhesion molecule (L1CAM) is known to play an oncogenic role in metastatic cancers, including CRPC. However, the impact of L1CAM on NEPC progression remains elusive. METHODS: L1CAM expression level was investigated using public gene expression databases of PC cohorts and patient-derived xenograft models. L1CAM knockdown was performed in different PC cells to study in vitro cell functions. A subline of CRPC cell line CWR22Rv1 was established after long-term exposure to abiraterone to induce NE differentiation. The androgen receptor-negative cell line PC3 was cultured under the tumor sphere-forming condition to enrich cancer stemness features. Several oxidative stress inducers were tested on PC cells to observe L1CAM-mediated gene expression and cell death. RESULTS: L1CAM expression was remarkably high in NEPC compared to CRPC or adenocarcinoma tumors. L1CAM was also correlated with NE marker expressions and associated with the adenocarcinoma-to-NEPC progression in gene expression databases and CRPC cells with NE differentiation. L1CAM also promoted cancer stemness and NE phenotypes in PC3 cells under cancer stemness enrichment. L1CAM was also identified as a reactive oxygen species-induced gene, by which L1CAM counteracted CRPC cell death triggered by ionizing radiation. CONCLUSIONS: Our results unveiled a new role of L1CAM in the acquisition of the NE phenotype in PC, contributing to the NE differentiation-related therapeutic resistance of CRPC.

Correlation analyses of radiographic progression-free survival with clinical and health-related quality of life outcomes in metastatic castration-resistant prostate cancer: Analysis of the phase 3 VISION trial.

BACKGROUND: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) plus protocol-permitted standard of care (SOC) prolonged overall survival (OS) and radiographic progression-free survival (rPFS) versus SOC in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 VISION study, in addition to beneficial effects on symptomatic skeletal events (SSEs) and health-related quality of life (HRQOL). METHODS: Post hoc analyses used the full analysis set from the VISION study (N = 831) overall and by randomized treatment arm (177Lu-PSMA-617 plus SOC, n = 551; SOC, n = 280). Correlations were determined between OS and rPFS and between rPFS or OS and time to SSE or to worsening HRQOL (Functional Assessment of Cancer Therapy-Prostate [FACT-P] and 5-level EQ-5D [EQ-5D-5L]). Correlation analyses used an iterative multiple imputation copula-based approach (correlation coefficients [rho] of <0.3 were defined as weak, ≥0.3 and <0.5 as mild, ≥0.5 and <0.7 as moderate, and ≥0.7 as strong). RESULTS: In the overall population, rPFS correlated strongly with OS (rho, ≥0.7). Correlations between rPFS or OS and time to SSE without death were weak or mild. Time to worsening in the FACT-P total score and emotional and physical well-being domains correlated mildly or moderately with rPFS and moderately with OS. Correlation coefficients for time-to-worsening EQ-5D-5L scores were mild to moderate for both rPFS and OS. Correlation coefficients were similar between treatment arms. CONCLUSIONS: In this analysis of the VISION study, rPFS correlated strongly with OS but not with time to SSE or worsening HRQOL. These findings require further investigation.

Extended Safety and Tolerability of Darolutamide for Nonmetastatic Castration-Resistant Prostate Cancer and Adverse Event Time Course in ARAMIS.

BACKGROUND: Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) are usually asymptomatic and seek treatments that improve survival but have a low risk of adverse events. Darolutamide, a structurally distinct androgen receptor inhibitor (ARi), significantly reduced the risk of metastasis and death versus placebo in ARAMIS. We assessed the extended safety and tolerability of darolutamide and the time-course profile of treatment-emergent adverse events (TEAEs) related to ARis and androgen-suppressive treatment. PATIENTS AND METHODS: Patients with nmCRPC were randomized 2:1 to darolutamide (n = 955) or placebo (n = 554). After trial unblinding, patients could receive open-label darolutamide. Tolerability and TEAEs were assessed every 16 weeks. Time interval-specific new and cumulative event rates were determined during the first 24 months of the double-blind period. RESULTS: Darolutamide remained well tolerated during the double-blind and open-label periods, with 98.8% of patients receiving the full planned dose. The incidence of TEAEs of interest in the darolutamide group was low and ≤2% different from that in the placebo group, except for fatigue. When incidences were adjusted for exposure time, there were minimal differences between the darolutamide double-blind and double-blind plus open-label periods. The rate of initial onset and cumulative incidence of grade 3/4 TEAEs and serious TEAEs were similar for darolutamide and placebo groups over 24 months. CONCLUSION: Extended treatment with darolutamide was well tolerated and no new safety signals were observed. Most ARi-associated and androgen-suppressive treatment-related TEAEs occurred at low incidences with darolutamide, were similar to placebo, and showed minimal increase over time with continued treatment. TRIAL NUMBER: ClinicalTrials.gov identifier NCT02200614.

Treatment patterns for patients with BRCA1/2-positive metastatic castration-resistant prostate cancer.

BACKGROUND: Patients with BRCA-positive metastatic castration-resistant prostate cancer (mCRPC) have an aggressive disease course. This study aimed to describe real-world treatment patterns among patients with BRCA-positive mCRPC. MATERIALS AND METHODS: De-identified electronic health record data from the Flatiron Health-Foundation Medicine Inc. Metastatic Prostate Cancer Clinico-Genomic Database (January 01, 2011 to June 30, 2022) were used to select patients with BRCA-positive mCRPC initiating first-line (1L) therapy with an oncologist-defined advanced line of therapy (LOT) or androgen deprivation therapy (ADT) monotherapy. Treatment sequences and reasons for censoring were described in 1L, and among patients who initiated a second-line (2L) therapy. RESULTS: A total of 98 treated patients with BRCA-positive mCRPC were identified. The top 3 treatment regimens in 1L, overall, were ADT monotherapy (19%), enzalutamide (14%), and olaparib (13%). The main reason for censoring patients with ADT monotherapy was death (52.6%). Among 79 patients treated with an advanced LOT in 1L, 43.0% (n = 34) did not initiate a 2L therapy, of which, 29.4% died. In patients who initiated a 2L (n = 45), the most common 1L to 2L treatment sequence was olaparib to docetaxel (11.1%). The most prescribed 2L therapies were docetaxel (22.2%), olaparib (20.0%), abiraterone acetate (13.3%), and enzalutamide (11.1%). From 1L initiation, the median time-to-next-treatment was 6.2 months. CONCLUSION: Among patients with BRCA-positive mCRPC, ADT monotherapy, enzalutamide, and olaparib were most commonly used. Prognosis of BRCA-positive patients was poor, with most patients failing initial therapy resulting in a switch to a new therapy or death. These findings highlight the need for earlier and more effective treatments for patients with BRCA-positive mCRPC.

A phase 2 study of AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Inhibition of the adenosine 2A receptor (A2AR) diminishes the immunosuppressive effects of adenosine and may complement immune-targeting drugs. This phase 2 study evaluated the A2AR antagonist AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer. METHODS: Patients with histologically/cytologically confirmed disease progressing within 6 months on ≥ 2 therapy lines were randomly assigned to either Module 1 (AZD4635 + durvalumab) or Module 2 (AZD4635 + oleclumab). Primary endpoints were objective response rate per RECIST v1.1 and prostate-specific antigen (PSA) response rate. Secondary endpoints included radiological progression-free survival (rPFS), overall survival, safety, and pharmacokinetics. RESULTS: Fifty-nine patients were treated (Module 1, n = 29; Module 2, n = 30). Median number of prior therapies was 4. One confirmed complete response by RECIST (Module 1) and 2 confirmed PSA responses (1 per module) were observed. The most frequent adverse events (AEs) possibly related to AZD4635 were nausea (37.9%), fatigue (20.7%), and decreased appetite (17.2%) in Module 1; nausea (50%), fatigue (30%), and vomiting (23.3%) in Module 2. No dose-limiting toxicities or treatment-related serious AEs were observed. In Module 1, AZD4635 geometric mean trough concentration was 124.9 ng/mL (geometric CV% 69.84; n = 22); exposures were similar in Module 2. In Modules 1 and 2, median (95% CI) rPFS was 2.3 (1.6 -3.8) and 1.5 (1.3- 4.0) months, respectively. Median PFS was 1.7 versus 2.3 months for patients with high versus low blood-based adenosine signature. CONCLUSION: In this heavily pretreated population, AZD4635 with durvalumab or oleclumab demonstrated minimal antitumor activity with a manageable safety profile. CLINICAL TRIAL: gov identifier: NCT04089553.

JMJD2A promotes the development of castration-resistant prostate cancer by activating androgen receptor enhancer and inhibiting the cGAS-STING pathway.

Exploring targets for inhibiting androgen receptor (AR) activity is an effective strategy for suppressing the development of castration-resistant prostate cancer (CRPC). Upregulation of histone demethylase JMJD2A activity is an important factor in increasing AR expression in CRPC. Based on our research, we found that the binding affinity between JMJD2A and AR increases in CRPC, while the level of AR histone methylation decreases and the H3K27ac level increases in the AR enhancer region. Further investigations revealed that overexpression of the histone demethylase JMJD2A increased the binding affinity between JMJD2A and AR, decreased AR histone methylation levels, upregulated H3K27ac in the AR enhancer region, and increased AR activity. Conversely, knocking down JMJD2A effectively reversed these effects. Additionally, in CRPC, JMJD2A expression was upregulated, the tumor-intrinsic immune cGAS-STING signaling pathway was suppressed, the tumor microenvironment was altered, and AR expression was upregulated. However, both knocking down JMJD2A and inhibiting the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS-STING) signaling pathway reversed these effects. In summary, our study indicates that in CRPC, JMJD2A can directly bind to AR and activate residual AR enhancers through its demethylation activity, thereby promoting AR expression. Furthermore, upregulation of JMJD2A expression inhibits the innate immune cGAS-STING signaling pathway of the tumor, leading to a decrease in antitumor immune function, and further promoting AR expression.

HuR promotes castration-resistant prostate cancer progression by altering ERK5 activation via posttranscriptional regulation of BCAT1.

BACKGROUND: Castration-resistant prostate cancer (CRPC) is refractory to hormone treatment, and the underlying mechanism has not been fully elucidated. This study aimed to clarify the role and mechanism of Human antigen R (HuR) as a therapeutic target for CRPC progression. METHODS: HuR was knocked out by Cas9 or inhibited by the HuR-specific inhibitor KH-3 in CRPC cell lines and in a mouse xenograft model. The effects of HuR inhibition on tumour cell behaviors and signal transduction were examined by proliferation, transwell, and tumour xenograft assays. Posttranscriptional regulation of BCAT1 by HuR was determined by half-life and RIP assays. RESULTS: HuR knockout attenuated the proliferation, migration, and invasion of PC3 and DU145 cells in vitro and inhibited tumour progression in vivo. Moreover, BCAT1 was a direct target gene of HuR and mediated the oncogenic effect of HuR on CRPC. Mechanistically, HuR directly interacted with BCAT1 mRNA and upregulated BCAT1 expression by increasing the stability and translation of BCAT1, which activated ERK5 signalling. Additionally, the HuR-specific inhibitor KH-3 attenuated CRPC progression by disrupting the HuR-BCAT1 interaction. CONCLUSIONS: We confirmed that the HuR/BCAT1 axis plays a crucial role in CRPC progression and suggest that inhibiting the HuR/BCAT1 axis is a promising therapeutic approach for suppressing CRPC progression.

Comparison of novel PSMA-targeting [177Lu]Lu-P17-087 with its albumin binding derivative [177Lu]Lu-P17-088 in metastatic castration-resistant prostate cancer patients: a first-in-human study.

PURPOSE: Prostate-specific membrane antigen (PSMA) is a promising target for diagnosis and radioligand therapy (RLT) of prostate cancer. Two novel PSMA-targeting radionuclide therapy agents, [177Lu]Lu-P17-087, and its albumin binder modified derivative, [177Lu]Lu-P17-088, were evaluated in metastatic castration-resistant prostate cancer (mCRPC) patients. The primary endpoint was dosimetry evaluation, the second endpoint was radiation toxicity assessment (CTCAE 5.0) and PSA response (PCWG3). METHODS: Patients with PSMA-positive tumors were enrolled after [68Ga]Ga-PSMA-11 PET/CT scan. Five mCRPC patients received [177Lu]Lu-P17-087 and four other patients received [177Lu]Lu-P17-088 (1.2 GBq/patient). Multiple whole body planar scintigraphy was performed at 1.5, 4, 24, 48, 72, 120 and 168 h after injection and one SPECT/CT imaging was performed at 24 h post-injection for each patient. Dosimetry evaluation was compared in both patient groups. RESULTS: Patients showed no major clinical side-effects under this low dose treatment. As expected [177Lu]Lu-P17-088 with longer blood circulation (due to its albumin binding) exhibited higher effective doses than [177Lu]Lu-P17-087 (0.151 ± 0.036 vs. 0.056 ± 0.019 mGy/MBq, P = 0.001). Similarly, red marrow received 0.119 ± 0.068 and 0.048 ± 0.020 mGy/MBq, while kidney doses were 0.119 ± 0.068 and 0.046 ± 0.022 mGy/MBq, respectively. [177Lu]Lu-P17-087 demonstrated excellent tumor uptake and faster kinetics; while [177Lu]Lu-P17-088 displayed a slower washout and higher average dose (7.75 ± 4.18 vs. 4.72 ± 2.29 mGy/MBq, P = 0.018). After administration of [177Lu]Lu-P17-087 and [177Lu]Lu-P17-088, 3/5 and 3/4 patients showed reducing PSA values, respectively. CONCLUSION: [177Lu]Lu-P17-088 and [177Lu]Lu-P17-087 displayed different pharmacokinetics but excellent PSMA-targeting dose delivery in mCRPC patients. These two agents are promising RLT agents for personalized treatment of mCRPC. Further studies with increased dose and frequency of RLT are warranted to evaluate the potential therapeutic efficacy. TRIAL REGISTRATION: 177Lu-P17-087/177Lu-P17-088 in Patients with Metastatic Castration-resistant Prostate Cancer (NCT05603559, Registered at 25 October, 2022). URL OF REGISTRY: https://classic. CLINICALTRIALS: gov/ct2/show/NCT05603559 .

Same-day post-therapy imaging with a new generation whole-body digital SPECT/CT in assessing treatment response to [177Lu]Lu-PSMA-617 in metastatic castration-resistant prostate cancer.

PURPOSE: Lutetium-177 [177Lu]Lu-PSMA-617 radioligand therapy (RLT) represents a significant advancement for metastatic castration-resistant prostate cancer (mCRPC), demonstrating improvements in radiographic progression free survival (rPFS) and overall survival (OS) with a low rate of associated side effects. Currently, most post-therapy SPECT/CT is conducted at 24 h after infusion. This study examines the clinical utility of a next-generation multi-detector Cadmium-Zinc-Telluride (CZT) SPECT/CT system (StarGuide) in same-day post-infusion assessment and early treatment response to [177Lu]Lu-PSMA-617. METHODS: In this retrospective study, 68 men with progressive mCRPC treated with [177Lu]Lu-PSMA-617 at our center from June 2022 to June 2023 were evaluated. Digital whole-body SPECT/CT imaging was performed after [177Lu]Lu-PSMA-617infusion (mean ± SD: 1.8 ± 0.6 h, range 1.1-4.9 h). Quantitative analysis of [177Lu]Lu-PSMA-617 positive lesions was performed in patients who underwent at least 2 post-therapy SPECT/CT, using liver parenchyma uptake as reference. Metrics including [177Lu]Lu-PSMA-617 positive total tumor volume (Lu-TTV), SUVmax and SUVmean were calculated. These quantitative metrics on post-infusion SPECT/CT images after cycles 1, 2 and 3 were correlated with overall survival (OS), prostate specific antigen-progression free survival (PSA-PFS) as defined by prostate cancer working group 3 (PCWG3), and PSA decrease over 50% (PSA50) response rates. RESULTS: 56 patients (means age 76.2 ± 8.1 years, range: 60-93) who underwent at least 2 post-therapy SPECT/CT were included in the image analysis. The whole-body SPECT/CT scans (~ 12 min per scan) were well tolerated, with 221 same-day scans performed (89%). At a median of 10-months follow-up, 33 (58.9%) patients achieved PSA50 after [177Lu]Lu-PSMA-617 treatment and median PSA-PFS was 5.0 months (range: 1.0-15 months) while median OS was not reached. Quantitative analysis of SPECT/CT images showed that 37 patients (66%) had > 30% reduction in Lu-TTV, associated with significantly improved overall survival (median not reached vs. 6 months, P = 0.008) and PSA-PFS (median 6 months vs. 1 months, P < 0.001). However, changes in SUVmax or SUVmean did not correlate with PSA-PFS or OS. CONCLUSION: We successfully implemented same-day post-therapy SPECT/CT after [177Lu]Lu-PSMA-617 infusions. Quantitation of 1-2 h post-therapy SPECT/CT images is a promising method for assessing treatment response. However, the approach is currently limited by its suboptimal detection of small tumor lesions and the necessity of incorporating a third-cycle SPECT/CT to mitigate the effects of any potential treatment-related flare-up. Further investigation in a larger patient cohort and prospective validation is essential to confirm these findings and to explore the role of SPECT/CT as a potential adjunct to PSMA PET/CT in managing mCRPC.

Analysis of the immune-inflammatory indices for patients with metastatic hormone-sensitive and castration-resistant prostate cancer.

BACKGROUND: Inflammation plays a pivotal role in the progression of prostate cancer (PCa). Several immune-inflammatory indices, including neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), lymphocyte to monocyte ratio (LMR) and platelet to lymphocyte ratio (PLR), lung immune prognostic index (LIPI), systemic inflammation response index (SIRI) and systemic immune inflammation index (SII), have demonstrated their prognostic values in several solid malignancies. However, Comparisons of superiority with these seven indices' predictive efficacy within metastatic hormone-sensitive PCa (mHSPC) and metastatic castration-resistant PCa (mCRPC) remain uncertain. METHODS: We retrospectively included 407 patients diagnosed with mHSPC and 158 patients with mCRPC at West China Hospital from 2005 to 2022. The seven immune-inflammatory indices were computed based on hematological data of mHSPC at initial diagnosis and mCRPC at progression to CRPC. Prognostic value for castration-resistant prostate cancer-free survival (CFS), overall survival (OS), prostate-specific antigen progression-free survival (PSA-PFS) and prostate-specific antigen (PSA) response was assessed using Kaplan-Meier curves, Cox regression models, and chi-square tests. The predictive performance of each immune-inflammatory index was assessed using the area under the curve (AUC) in time-dependent receiver operating characteristic curve (ROC) analysis and C-index calculation. RESULTS: All seven immune-inflammatory indices were significantly associated with CFS and OS in the mHSPC cohort, as well as with PSA response, PSA-PFS, and OS in the mCRPC cohort. In the mHSPC cohort, LIPI consistently exhibited higher AUC values compared to NLR, dNLR, LMR, PLR, SII, and SIRI for predicting CFS and OS. This indicates that LIPI had a superior discriminative ability compared to the other indices (C-index of LIPI: 0.643 and 0.686 for CFS and OS, respectively). Notably, the predictive advantage of LIPI over other indices in the mHSPC stage diminished in the mCRPC stage. CONCLUSIONS: This study firstly confirmed the prognostic value of SII, SIRI and LIPI in mHSPC and mCRPC, and revealed that LIPI had a higher predictive power than NLR, dNLR, LMR, PLR, SII and SIRI in mHSPC. These non-invasive indices can enable clinicians to quickly assess the prognosis of patients.