Enzalutamide Enhances PSMA Expression of PSMA-Low Prostate Cancer.
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ABSTRACT:
SUBMITTER: Staniszewska M
PROVIDER: S-EPMC8304389 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The refractory of castration-resistant prostate cancer (CRPC) is mainly reflected in drug resistance. The current research on the resistance mechanism of CRPC is still in its infancy. In this study, we revealed for the first time the key role of LncRNA PCBP1-AS1 in CRPC drug resistance. Through detailed in vivo and in vitro studies, we found that PCBP1-AS1 may enhance the deubiquitination of AR/AR-V7 by stabilizing the USP22-AR/AR-V7 complex, thereby preventing AR/AR-V7 from being degraded through the ubiquitin-proteasome pathway. Targeting PCBP1-AS1 can significantly restore the drug sensitivity of enzalutamide-resistant tumors in vivo and in vitro. Our research further expands the function of LncRNA in castration-resistant prostate cancer, which may provide new potential for clinical diagnosis and targeted therapy.
| S-EPMC8452729 | biostudies-literature
Project description:Enzalutamide is a second-generation anti-androgen which has shown increased survival in patients with metastatic prostate cancer. However, some patients do not respond to this therapy or will develop resistance to treatment over time. Signal Transducer and Activator of Transcription 3 (STAT3) is known to be involved in castration-resistant prostate cancer and to interact with androgen receptor (AR)-signaling. This study aims to investigate the combination enzalutamide and the small molecule STAT3 inhibitor GPB730 for enhanced therapeutic effect in advanced prostate cancer in vitro. The prostate cancer cell lines LNCaP (androgen dependent) and C4-2 (androgen insensitive) were used. The effect of enzalutamide and GPB730, alone and in combination, was investigated on viability and IC50 values calculated. Enzalutamide and GPB730 treated LNCaP and C4-2 cells were subjected to western blot and QPCR analyses in order to investigate the expression of AR, STAT3 and down-stream targets. C4-2 were less sensitive to growth inhibition by enzalutamide than LNCaP cells. GPB730 enhanced the growth inhibitory effect of enzalutamide in LNCaP and C4-2 cells. The addition of GPB730 to enzalutamide decreased the IC50 values for enzalutamide by 3.3-fold for LNCaP and by 12-fold for C4-2. In C4-2 cells, GPB730 alone decreased PSA expression and enhanced the enzalutamide induced decrease in NKX3.1 expression. GPB730 and enzalutamide in combination enhanced inhibition of c-myc and survivin expression. This study suggests that enzalutamide may be combined with the STAT3 inhibitor GPB730 in order to enhance the efficacy of enzalutamide, offering a new therapeutic approach in advanced prostate cancer.
| S-EPMC9344336 | biostudies-literature
Project description:Enhanced vascular permeability in tumors plays an essential role in nanoparticle delivery. Prostate-specific membrane antigen (PSMA) is overexpressed on the epithelium of aggressive prostate cancers (PCs). Here, we evaluated the feasibility of increasing the delivery of PSMA-targeted magnetic nanoparticles (MNPs) to tumors by enhancing vascular permeability in PSMA(+) PC tumors with PSMA-targeted photodynamic therapy (PDT). Method: PSMA(+) PC3 PIP tumor-bearing mice were given a low-molecular-weight PSMA-targeted photosensitizer and treated with fluorescence image-guided PDT, 4 h after. The mice were then given a PSMA-targeted MNP immediately after PDT and monitored with fluorescence imaging and T2-weighted magnetic resonance imaging (T2-W MRI) 18 h, 42 h, and 66 h after MNP administration. Untreated PSMA(+) PC3 PIP tumor-bearing mice were used as negative controls. Results: An 8-fold increase in the delivery of the PSMA-targeted MNPs was detected using T2-W MRI in the pretreated tumors 42 h after PDT, compared to untreated tumors. Additionally, T2-W MRIs revealed enhanced peripheral intra-tumoral delivery of the PSMA-targeted MNPs. That finding is in keeping with two-photon microscopy, which revealed higher vascular densities at the tumor periphery. Conclusion: These results suggest that PSMA-targeted PDT enhances the delivery of PSMA-targeted MNPs to PSMA(+) tumors by enhancing the vascular permeability of the tumors.
| S-EPMC7868004 | biostudies-literature
Project description:The FDA approval of docetaxel for metastatic castration-resistant prostate cancer (mCRPC) in 2005 marked a major milestone, as it was the first approved agent for this disease that demonstrated a survival advantage in Phase III assessment of this disease. Since 2009, several other agents have been approved by FDA, including sipuleucel-T, abiraterone, cabazitaxel and enzalutamide . Enzalutamide, a potent antiandrogen that blocks nuclear translocation of the androgen receptor (AR), is the most recently approved of these agents.The clinical development of enzalutamide is discussed, with attention given as to how this agent will most appropriately be used among a growing list of agents for mCRPC. A MEDLINE search was conducted to identify all relevant published datasets pertaining to the drug. In addition, relevant ASCO and ESMO abstracts were searched.The current role and sequencing of enzalutamide may change drastically based on studies such as PREVAIL (a Phase III pre-chemotherapy assessment of enzalutamide) and planned studies to assess relevant combinations (i.e., enzalutamide with abiraterone). Outside of clinical efficacy, issues such as drug cost may ultimately dictate our utilization of agents such as enzalutamide for mCPRC. Although the development of biomarkers to guide therapy for mCRPC is ideal, there are inherent challenges in establishing biomarker-driven treatment.
| S-EPMC3845878 | biostudies-other
Project description:PurposeIn men with metastatic castration-resistant prostate cancer (mCRPC), prostate-specific membrane antigen (PSMA)-targeted radioligand therapy has drastically improved clinical outcomes. A liquid biopsy characterizing PSMA expression could be useful in guiding optimal therapy.Experimental designWe conducted a retrospective analysis of the prospective multicenter PROPHECY (Prospective CiRculating PrOstate Cancer Predictors in HighEr Risk mCRPC StudY) trial of men with mCRPC (n = 118) treated with abiraterone (abi) or enzalutamide (enza). Circulating tumor cells (CTC) were enriched (CTC/mL) and characterized for PSMA protein expression/heterogeneity at baseline and progression. We utilized proportional hazards modeling of the association between PSMA-positive (PSMA+) CTC enumeration with overall survival (OS) and progression-free survival (PFS).ResultsOverall, 97 men with mCRPC had evaluable blood samples for baseline CTC PSMA detection; 78 men (80%) had detectable CTCs. Of these, 55% (43/78) of men had any PSMA CTC detection, 21% (16/78) had ≥2 PSMA+ CTCs/mL, and 19% (8/43) were 100% PSMA+. At progression on abi/enza, 88% (50/57) of men had detectable CTCs, 68% (34/50) had any PSMA CTCs, and 12% (4/34) had 100% PSMA+ CTCs. Among paired cases (n = 57), PSMA+ CTC detection increased slightly after abi/enza progression. Using an optimal cutoff of ≥2 PSMA+ CTCs/mL, median OS was 26, 21, and 11 months for men without CTCs, PSMA- CTCs, and PSMA+ CTCs. Adjusting for prior abi/enza therapy, Halabi clinical risk score, and CTC enumeration, the HRs for OS and PFS for PSMA+ CTC+ were 3.0 [95% confidence interval (CI) = 1.1-7.8] and 2.3 (95% CI = 0.9-5.8).ConclusionsWe observed PSMA CTC heterogeneity between and within patients with mCRPC over time during abi/enza progression. CTC PSMA enumeration was adversely prognostic independent of clinical factors and disease burden. Further validation is warranted in the context of PSMA-targeted therapies.
| S-EPMC10192124 | biostudies-literature
Project description:BackgroundEnzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy.MethodsIn this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival.ResultsThe study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment.ConclusionsEnzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).
| S-EPMC4418931 | biostudies-literature
Project description:BackgroundPSMA expression in the prostate epithelium is controlled by a cis-element, PSMA enhancer (PSME). PSME contains multiple binding sites for Sox proteins, and in this study, we identified Sox7 protein as a negative regulator of PSMA expression through its interaction with PSME.MethodsThe statistical correlation between Sox7 and PSMA mRNA expression was evaluated using five prostate cancer studies from cBioportal. In vitro and in vivo interaction between Sox7 and PSME was evaluated by chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), and luciferase reporter assay. Synthetic oligonucleotides were generated to define the sites in PSME that interact with Sox7 protein. Sox7 mutants were generated to identify the region of this protein required to regulate PSMA expression. Sox7 was also stably expressed in LNCaP/C4-2 and 22Rv1 cells to validate the regulation of PSMA expression by Sox7 in vivo.ResultsSox7 mRNA expression negatively correlated with PSMA/FOLH1 and PSMAL/FOLH1B mRNA expression in Broad/Cornell, TCGA and MSKCC studies, but not in two studies containing only metastatic prostate tumors. PC-3 cells mostly expressed the 48.5 KDa isoform 2 of Sox7, and the depletion of this isoform did not restore PSMA expression. Ectopic expression of canonical, wild-type Sox7 in C4-2 and 22Rv1 cells suppressed PSMA protein expression. ChIP assay revealed that canonical Sox7 protein preferentially interacts with PSME in vivo, and EMSA identified the SOX box sites #2 and #4 in PSME as required for its interaction. Sox7 was capable of directly binding to PSME and suppressed PSME-mediated transcription. The NLS regions of Sox7, but not its β-catenin interacting motif, are essential for this suppressing activity. Furthermore, restoration of wild-type Sox7 expression but not Sox7-NLS mutant in Sox7-null prostate cancer cell lines suppressed PSMA expression.ConclusionsThe inactivation of canonical Sox7 is responsible for the upregulated expression of PSMA in non-metastatic prostate cancer.
| S-EPMC6344945 | biostudies-literature
Project description:ObjectivesPSMA (prostate-specific membrane antigen) is overexpressed in prostate cancer cells and is reported to be a promising target for antibody-based radioligand therapy in patients with metastasized prostate cancer. Since PSMA expression is not restricted to prostate cancer, the underlying study investigates PSMA expression in non-small cell lung cancer (NSCLC).Material and methodsImmunohistochemistry was used to identify PSMA expression in n = 275 samples of NSCLC tissue specimens. By means of CD34 co-expression, the level of PSMA expression in tumor associated neovasculature was investigated. The impact of PSMA expression on clinicopathologic parameters and prognosis was evaluated.ResultsPSMA tumor cell expression in NSCLC is as low as 6% and was predominantly found in squamous cell carcinoma (p = 0.002). Neovascular PSMA expression was found in 49% of NSCLC. High neovascular PSMA expression was associated with higher tumor grading (G3/G4) (p < 0.001). Neither for PSMA tumor cell expression, nor for PSMA neovascular cell expression prognostic effects were found for the investigated NSCLC cases.ConclusionHere, we report on the expression of PSMA in NSCLC tissue samples. Against the background of a potential treatment with radiolabeled PSMA ligands, our data might serve for the future identification of patients who could benefit from this therapeutic option.
| S-EPMC5659610 | biostudies-literature
Project description:Prostate-specific membrane antigen (PSMA) is an important cell surface target in prostate cancer. There are limited data on the heterogeneity of PSMA tissue expression in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, the mechanisms regulating PSMA expression (encoded by the FOLH1 gene) are not well understood. Here, we demonstrate that PSMA expression is heterogeneous across different metastatic sites and molecular subtypes of mCRPC. In a rapid autopsy cohort in which multiple metastatic sites per patient were sampled, we found that 13 of 52 (25%) cases had no detectable PSMA and 23 of 52 (44%) cases showed heterogeneous PSMA expression across individual metastases, with 33 (63%) cases harboring at least 1 PSMA-negative site. PSMA-negative tumors displayed distinct transcriptional profiles with expression of druggable targets such as MUC1. Loss of PSMA was associated with epigenetic changes of the FOLH1 locus, including gain of CpG methylation and loss of histone 3 lysine 27 (H3K27) acetylation. Treatment with histone deacetylase (HDAC) inhibitors reversed this epigenetic repression and restored PSMA expression in vitro and in vivo. Collectively, these data provide insights into the expression patterns and regulation of PSMA in mCRPC and suggest that epigenetic therapies - in particular, HDAC inhibitors - can be used to augment PSMA levels.
| S-EPMC10132157 | biostudies-literature
Project description:To review and evaluate current literature on the US Food and Drug Administration (FDA)-approved drug enzalutamide (XTANDI(®)) in metastatic castration-resistant prostate cancer.Literature search was done through PubMed using the terms enzalutamide, MDV3100, abiraterone, and castration-resistant prostate cancer. Data from FDA product labels were also used.Recent and relevant studies were included in the review. Collected clinical trials were screened and evaluated.Enzalutamide is an androgen receptor (AR) inhibitor with high selectivity and affinity to the AR. It was approved by the FDA to treat metastatic castration-resistant prostate cancer in patients previously treated with docetaxel, after a Phase III trial (AFFIRM) that showed a 4.8-month survival benefit in this population. Recently, the FDA expanded the approval of enzalutamide as first-line therapy for metastatic castration-resistant prostate cancer (mCRPC) who did not receive chemotherapy. Moreover, enzalutamide is shown to be associated with an acceptable safety profile.Enzalutamide has been shown to be both safe and effective in improving overall survival in metastatic castration-resistant prostate cancer postchemotherapy with docetaxel and as a first line treatment before initiation of chemotherapy. However, additional studies and head-to-head trials are needed.
| S-EPMC4407758 | biostudies-other