Clinical Management Of Prostate Cancer Research Articles

Abstract 2423: Linking liquids: cfDNA in urine and plasma as informative allies in metastasized prostate cancer

Abstract Background: Liquid biopsy has become a cornerstone of non-invasive cancer diagnostics. While the major analyte for detecting and monitoring tumors has been blood, examining other body fluids, such as urine or saliva, is increasingly shifting into focus. Urine is a particularly valuable specimen due to its easy accessibility. Particularly in urologic cancers, the sensitivity of liquid biopsy could be improved by proximal sampling. While there is already evidence that cell-free DNA from urine (ucfDNA) can add to the diagnostic sensitivity in renal and bladder cancer, less is known about ucfDNA in prostate cancer patients. In this study, we aimed to determine the presence, levels, and potential clinical applications of ucfDNA in patients with metastatic prostate cancer. Moreover, we compared the findings with information obtained from plasma cell-free DNA (cfDNA). Methods: Urine was collected and stabilized using the PAXgene Urine Liquid Biopsy Set or STRECK as a preservative. The collection and stabilization using PAXgene Urine Liquid Biopsy Set allows a standardized collection and stabilization of urine with fixed volumes of urine and preservatives. Blood was collected in PAXgene Blood ccfDNA Tubes (PreAnalytiX). Matched blood and urine cfDNA samples from 122 metastatic prostate cancer patients were isolated using the QIAsymphony platform. Tumor fraction and presence of somatic copy number alterations (SCNA) were assessed from shallow whole genome sequencing data using the ichorCNA algorithm. Results: In 22/122 (18%) of patients SCNAs could be detected in both, urine and blood. Although the copy number profile was highly concordant in those patients, tumor fractions varied between plasma and urines on an individual patient level. In addition, in 52/122 (43%) and 48/122 (39%) patients, tumor-derived DNA was detected only in plasma or urine. Considering the entire cohort, neither the absolute cfDNA concentration nor tumor fraction did significantly differ between urine and plasma samples. Conclusion: Our data demonstrate that ucfDNA can provide complementary information to blood about prostate tumors, which would be missed by the sole analysis of plasma cfDNA. Taking this into account and adding that urine represents a non-invasive specimen type that can be collected at great ease, ucfDNA holds promise in the clinical management of prostate cancer. Citation Format: Tina Moser, Anna Eberhard, Matthias J. Moser, Lisa Glawitsch, Sabrina Hammer, Georgios Vlachos, Isaac Lazzeri, Leandra Ziegler, Emil Bauernhofer, Nina Monsberger, Jochen B. Geigl, Thomas Bauernhofer, Ellen Heitzer. Linking liquids: cfDNA in urine and plasma as informative allies in metastasized prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2423.

From molecular mechanisms of prostate cancer to translational applications: based on multi-omics fusion analysis and intelligent medicine.

Prostate cancer is the most common cancer in men worldwide and has a high mortality rate. The complex and heterogeneous development of prostate cancer has become a core obstacle in the treatment of prostate cancer. Simultaneously, the issues of overtreatment in early-stage diagnosis, oligometastasis and dormant tumor recognition, as well as personalized drug utilization, are also specific concerns that require attention in the clinical management of prostate cancer. Some typical genetic mutations have been proved to be associated with prostate cancer's initiation and progression. However, single-omic studies usually are not able to explain the causal relationship between molecular alterations and clinical phenotypes. Exploration from a systems genetics perspective is also lacking in this field, that is, the impact of gene network, the environmental factors, and even lifestyle behaviors on disease progression. At the meantime, current trend emphasizes the utilization of artificial intelligence (AI) and machine learning techniques to process extensive multidimensional data, including multi-omics. These technologies unveil the potential patterns, correlations, and insights related to diseases, thereby aiding the interpretable clinical decision making and applications, namely intelligent medicine. Therefore, there is a pressing need to integrate multidimensional data for identification of molecular subtypes, prediction of cancer progression and aggressiveness, along with perosonalized treatment performing. In this review, we systematically elaborated the landscape from molecular mechanism discovery of prostate cancer to clinical translational applications. We discussed the molecular profiles and clinical manifestations of prostate cancer heterogeneity, the identification of different states of prostate cancer, as well as corresponding precision medicine practices. Taking multi-omics fusion, systems genetics, and intelligence medicine as the main perspectives, the current research results and knowledge-driven research path of prostate cancer were summarized.

Abstract B004: Dealing with prostate cancer racial disparity: Galeterone and next-generation galeterone analog VNPP433-3β potently inhibits proliferation of prostate cancer cells from African American patient by degrading AR and Mnk1/2

Abstract Prostate cancer incidence and mortality rates are remarkably higher in African-American (AA) men as compared to their European-American (EA) counterparts even after factoring in socio economic status. The disproportionate incidence of prostate cancer and associated mortality in African men is currently becoming more evident as Several studies have reported significant variations in genetic, molecular, epigenetic, microRNA, and cell signaling pathways in patients of Caucasian and African race. As androgen is implicated in prostate cancer progression and about 90% of the cases are Androgen-dependent, blocking androgen action is an effective strategy in treating prostate cancer. Previously, we reported that galeterone and VNPP433-3β, a next generation galeterone analog potently inhibit metastatic castration resistant prostate cancer of Caucasian origin in vitro and in vivo by degrading AR/AR-V7 and Mnk1/2. Since the prostate cancer patients of African descent express significant levels of AR and Mnk1/2, we investigated the efficacy of galeterone and VNPP433-3β in treating prostate cancer of African men. Cell proliferation assay using the cell lines MDA-PCa 2b and RC77 T/E derived from AA prostate cancer patient demonstrates that galeterone and VNPP433-3β can effectively inhibit prostate cancer of African descent at very low concentration. These cell lines are Androgen-sensitive and further biochemical studies reveal that galeterone and VNPP433-3β degrade AR and Mnk1/2 in RC77 T/E and MDA-PCa 2b cell lines, thereby inhibiting its proliferation. Galeterone and VNPP433-3β significantly decrease the half-life of AR in these cell lines by increasing the rate of ubiquitination and proteasomal degradation of AR. Therefore, galeterone and VNPP433-3β hold significant promise for the clinical management of prostate cancer in patients of African descent Citation Format: Elizabeth Thomas, Retheesh Sulochana Thankan, Puranik Purushottachar, Vincent C.O. Njar. Dealing with prostate cancer racial disparity: Galeterone and next-generation galeterone analog VNPP433-3β potently inhibits proliferation of prostate cancer cells from African American patient by degrading AR and Mnk1/2 [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B004.

PCa-Clf: A Classifier of Prostate Cancer Patients into Patients with Indolent and Aggressive Tumors Using Machine Learning

A critical unmet medical need in prostate cancer (PCa) clinical management centers around distinguishing indolent from aggressive tumors. Traditionally, Gleason grading has been utilized for this purpose. However, tumor classification using Gleason Grade 7 is often ambiguous, as the clinical behavior of these tumors follows a variable clinical course. This study aimed to investigate the application of machine learning techniques (ML) to classify patients into indolent and aggressive PCas. We used gene expression data from The Cancer Genome Atlas and compared gene expression levels between indolent and aggressive tumors to identify features for developing and validating a range of ML and stacking algorithms. ML algorithms accurately distinguished indolent from aggressive PCas. With the accuracy of 96%, the stacking model was superior to individual ML algorithms when all samples with primary Gleason Grades 6 to 10 were used. Excluding samples with Gleason Grade 7 improved accuracy to 97%. This study shows that ML algorithms and stacking models are powerful approaches for the accurate classification of indolent versus aggressive PCas. Future implementation of this methodology may significantly impact clinical decision making and patient outcomes in the clinical management of prostate cancer.

Nicardipine is a putative EED inhibitor and has high selectivity and potency against chemoresistant prostate cancer in preclinical models.

It is imperative to develop novel therapeutics to overcome chemoresistance, a significant obstacle in the clinical management of prostate cancer (PCa) and other cancers. A phenotypic screen was performed to identify novel inhibitors of chemoresistant PCa cells. The mechanism of action of potential candidate(s) was investigated using in silico docking, and molecular and cellular assays in chemoresistant PCa cells. The in vivo efficacy was evaluated in mouse xenograft models of chemoresistant PCa. Nicardipine exhibited high selectivity and potency against chemoresistant PCa cells via inducing apoptosis and cell cycle arrest. Computational, molecular, and cellular studies identified nicardipine as a putative inhibitor of embryonic ectoderm development (EED) protein, and the results are consistent with a proposed mechanism of action that nicardipine destabilised enhancer of zeste homologue 2 (EZH2) and inhibited key components of noncanonical EZH2 signalling, including transducer and activator of transcription 3, S-phase kinase-associated protein 2, ATP binding cassette B1, and survivin. As a monotherapy, nicardipine effectively inhibited the skeletal growth of chemoresistant C4-2B-TaxR tumours. As a combination regimen, nicardipine synergistically enhanced the in vivo efficacy of docetaxel against C4-2 xenografts. Our findings provided the first preclinical evidence supporting nicardipine as a novel EED inhibitor that has the potential to be promptly tested in PCa patients to overcome chemoresistance and improve clinical outcomes.

Abstract B073: Inhibiting prostate cancer by targeting the metabolic mevalonate pathway

Abstract Background: A major challenge in the clinical management of prostate cancer (PCa) is inhibiting progression to lethal castrate-resistant PC (CRPC). Deregulated activity of mevalonate (MVA), cholesterol biosynthetic pathway is a recognized hallmark of PCa cells. Statins are potent inhibitors of this metabolic pathway that have been used for decades in the control of hypercholesterolemia. Statins have recently been shown to have anti-PCa activity, however statin treatment triggers a feedback response that restores the MVA pathway, which reduces statin efficacy and contributes to resistance. This restorative feedback loop is controlled by the transcriptional activity of sterol regulatory-element binding protein (SREBP), which primarily induces fatty acid biosynthesis and MVA pathway genes. We have recently identified the anti-platelet agent dipyridamole (DP) as an inhibitor of the statin-induced SREBP-mediated feedback response. However, DP is not SREBP-specific and given its anti-platelet activity, may not be suitable for every cancer patient. Thus, our goal was to identify additional drugs that potentiate the pro-apoptotic activity of statins, which can be used to treat PCa patients. Methods: Two independent, yet complimentary strategies were used. The first focused on performing an in silico analysis to identify drugs that had similar properties to DP at the level of drug structure, molecular perturbations and cell line sensitivity. The second strategy involved a high-content imaging analysis of 1508 FDA approved drugs, which was performed in LNCaP (relatively statin insensitive and feedback competent) and PC3 cells (statin sensitive and feedback incompetent). Cells were treated with a sub-lethal dose of fluvastatin, the drugs or the fluvastatin-drug combination, then treated with apoptotic stains (TMRE, Annexin, Draq 5). Captured images were analyzed using a machine learning approach. Results: Validation of hits from the in silico MVA-DNF approach and high-content screening has identified several drugs that fulfill our criteria of potentiating statin-induced cell death in a feedback-dependent or feedback-independent manner. Interestingly, many show higher Z-scores compared to DP indicating their superior statin potentiation activity to drive PCa cell death. Moreover, a sub-set of these drug significantly inhibit statin-triggered expression of MVA pathway genes HMGCS1 and INSIG1 (p < 0.001) more potently than DP. Conclusions: We have detailed two successful strategies to identify drugs that inhibit SREBP activation in response to statin treatment. These statin-drug combinations represent an effective ‘one-two punch’ to inhibit CRPC progression. These novel inhibitors of SREBP activation potentiate statin at clinically relevant concentrations more potently than DP and have no effect on the platelet activity. Excitingly, many of these agents are FDA-approved and can be immediately used in combination with statins for the treatment of PCa. Overall, our research will lead to novel therapies to improve patient outcome. Citation Format: Diandra Zipinotti dos Santos, Mohamad Elbaz, Emily Branchard, Wiebke Schormann, David W. Andrews, Linda Z. Penn. Inhibiting prostate cancer by targeting the metabolic mevalonate pathway [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B073.

Clinical Efficacy of Vaccaria Segetalis Seeds and Gleditsia Sinensis Lam Thorns on Prostate Cancer: A Preliminary Mechanism Analysis Based on Network Pharmacology

Objective: The mechanism of Vaccaria segetalis (VS) seeds and Gleditsia sinensis Lam (GS) thorns in the treatment of prostate cancer (PC) was analyzed via network pharmacological analysis methods and molecular docking. Methods: The Traditional Chinese Medicine Systems Pharmacology Database Platform (TCMSP) was used to screen the PC’s effective components and targets; GeneCards and OMIM databases to search for targets related to PC. The intersection target was uploaded to the STRING database to obtain a proteinprotein interaction (PPI) network; and the key targets were screened from the PPI network via R language, CytoNCA, and CytoHubba tools. Gene Ontology (GO) and Kyoto encyclopedia of genes and genome (KEGG) pathway enrichment tools were used to analyze biological processes and molecular docking of key targets via AutoDock Vina software. Results: A total of 13 compounds, 229 nodes, 879 edges, and 20 key targets were obtained through the PPI network. Go and KEGG analysis showed that the intersection targets of VS and GS with PC were mainly involved in regulating cell promotion, cell apoptosis, cell cycle, and reversing epithelialmesenchymal transition (EMT) processing. Molecular docking revealed that the relevant targets of potential PC were characterized with stabilized affinity. Specifically, the targets with better affinity included estrogen receptor 1 (ESR1) with kaempferol, transcription factor p65 (RELA) with fisetin, kaempferol, quercetin, and mitogen-activated protein kinase 1 (MAPK1) with fisetin, and G1/S-specific cyclin-D1 (CCND1) with fisetin, kaempferol, and quercetin. Conclusion: In summary, this study reveals potential molecular therapeutic mechanisms of VS and GS in PC and provides a reference for the wide application of VS and GS in the clinical management of PC.

Genetic and Genomic Testing for Prostate Cancer: Beyond DNA Repair

Significant progress has been made in genetic and genomic testing for prostate cancer across the disease spectrum. Molecular profiling is increasingly relevant for routine clinical management, fueled in part by advancements in testing technology and integration of biomarkers into clinical trials. In metastatic prostate cancer, defects in DNA damage response genes are now established predictors of benefit to US Food and Drug Administration-approved poly (ADP-ribose) polymerase inhibitors and immune checkpoint inhibitors, and trials are actively investigating these and other targeted treatment strategies in earlier disease states. Excitingly, opportunities for molecularly informed management beyond DNA damage response genes are also maturing. Germline genetic variants (eg, BRCA2 or MSH2/6) and polygenic germline risk scores are being investigated to inform cancer screening and active surveillance in at-risk carriers. RNA expression tests have recently gained traction in localized prostate cancer, enabling patient risk stratification and tailored treatment intensification via radiotherapy and/or androgen deprivation therapy for localized or salvage treatment. Finally, emerging minimally invasive circulating tumor DNA technology promises to enhance biomarker testing in advanced disease pending additional methodological and clinical validation. Collectively, genetic and genomic tests are rapidly becoming indispensable tools for informing the optimal clinical management of prostate cancer.

Stereotactic Ablative Radiation Therapy in 3 Fractions Induces a Favorable Systemic Immune Cell Profiling in Prostate Cancer Patients

ABSTRACT The impact of radiotherapy (RT) on immune cell status in prostate cancer (PCa) is only partially determined. The aim of this study was to assess the effect of different RT strategies on peripheral B, T, and Natural killer (NK) lymphocytes at precise longitudinal time-points in PCa. 18 patients treated with stereotactic body radiation therapy (SBRT) (40 Gy/3FRX), definitive moderate-hypofractionation (62 Gy/20FRX), or post-operative conventional-fractionation RT (66–69 Gy/30FRX) were prospectively evaluated for the immune cell profile in terms of immune cell composition, differentiation stage, cytokine production and inhibitory receptor (IR) expression. The immune-monitoring of the 18 patients revealed that RT affects the balance of systemic immune cells, with the main differences observed between SBRT and conventionally fractionated RT. SBRT favorably impacts immune response in term of increased B cells, central-memory and effector-memory CD8+ T cells, along with decreased Treg cells after treatment. On the contrary, conventional fractionated RT had a long-term negative effect on the systemic immune profile, including a decrease of total lymphocyte counts accompanied by an increase of neutrophils-to-lymphocytes ratio. Total B and T cells decreased and Treg-to-CD8+ ratio increased. Functionality of T lymphocytes were not affected by any of the 3-fractionation schedules. Interestingly, SBRT significantly up-regulates the expression of V-domain immunoglobulin suppressor of T-cell activation (VISTA) in CD8+ T cells in the absence of other IRs. Our results indicate the relevance of systematic immunomonitoring during RT to identify novel immune-related target to design trials of combined radio-immunotherapy as a promising strategy in the clinical management of PCa.

Current role of PSMA-PET imaging in the clinical management of prostate cancer.

Despite the developments of the last few years, metastatic castration-resistant prostate cancer (PC) remains a deadly disease. Until recently, almost all guidelines recommended magnetic resonance imaging (MRI) or computed tomography (CT) for the initial staging and local/systematic recurrence. Positron emission tomography/computed tomography (PET/CT) with prostate-specific membrane antigen (PSMA) at the present stage, emerged as a promising diagnostic imaging tool for PC. PSMA PET/CT alone or in combination with multiparametric magnetic resonance imaging (mpMRI) can improve the detection of clinically significant PC, especially for Prostate Imaging Reporting & Data System (PI-RADS) = 3 lesions. In addition, PSMA PET/CT is more accurate than CT and bone scan for intermediate to high-risk disease at the initial staging. Contrariwise, a negative PET is not useful for surgeons to avoid a pelvic nodal dissection. PET-PSMA imaging is appropriate for prostate-specific antigen (PSA) persistence or PSA rise from undetectable level after radical prostatectomy or for PSA rise above nadir after definitive radiotherapy. Also, it is recommended for patients fit for curative salvage treatment. It should be noted that in patients, candidates for radionuclide therapy with Lutetium-177 (117Lu), a PSMA strong expression from PET/CT at baseline is considered necessary. This review summarizes the evolution of PSMA PET/CT and its current role in the management of PC.

Epigenetics-based diagnostic and therapeutic strategies: shifting the paradigm in prostate cancer

Despite recent advances, prostate cancer (PCa) remains a leading cause of cancer morbidity and mortality. Clinically, PCa screening methods display low sensitivity and specificity, leading to suboptimal patient care. Recent research suggests that PCa progression is regulated by a coordinated spectrum of epigenetic alterations that notably involves noncoding RNAs. These molecular aberrations drive PCa progression by inducing gene expression programs that promote metastatic dissemination. Epigenetic proteins and noncoding RNAs can be detected noninvasively in body fluids, allowing improved PCa screening and prognosis. In addition, epigenetic alterations can be targeted pharmacologically, providing unprecedented therapeutic opportunities. This work reviews the current literature linking epigenetic dysregulation and PCa progression and proposes a framework for integrating epigenetic strategies into the clinical management of PCa.

Understanding about Image-guided Detection of Prostate Cancer

The prostate is both an accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. Anatomically, the prostate is found below the bladder, with the urethra passing through it. Prostate cancer (PCa) is the second-most prevalent cancer and the fifth leading cause of cancer-specific mortality in male, worldwide. Currently, the only sure way to confirm prostate cancer is through a prostate biopsy. Rapid technological advances over the past few years have enabled the mainstream use of prostate imaging for the clinical management of prostate cancer. In biopsy for the diagnosis of prostate cancer, prostate imaging technology is mobilized to extract tissue from the exact area. Ultrasound imaging, MRI, and PET imaging methods are used for prostate imaging methods. Although each image has its own characteristics, the recent trend is the fusion image method that uses each other's strengths. There is currently no technology that can fully meet the clinical requirements of speed and high precision at the same time at a low cost. The development of a biopsy framework that is inexpensive, easy to use, and has minimal clinical overhead seems necessary. This requires the implementation of new image registration and visualization approaches and the establishment of a research platform for rapid bench-to-bed conversion.

Combining Molecular Subtypes with Multivariable Clinical Models Has the Potential to Improve Prediction of Treatment Outcomes in Prostate Cancer at Diagnosis.

Clinical management of prostate cancer is challenging because of its highly variable natural history and so there is a need for improved predictors of outcome in non-metastatic men at the time of diagnosis. In this study we calculated the model score from the leading clinical multivariable model, PREDICT prostate, and the poor prognosis DESNT molecular subtype, in a combined expression and clinical dataset that were taken from malignant tissue at prostatectomy (n = 359). Both PREDICT score (p < 0.0001, IQR HR = 1.59) and DESNT score (p < 0.0001, IQR HR = 2.08) were significant predictors for time to biochemical recurrence. A joint model combining the continuous PREDICT and DESNT score (p < 0.0001, IQR HR = 1.53 and 1.79, respectively) produced a significantly improved predictor than either model alone (p < 0.001). An increased probability of mortality after diagnosis, as estimated by PREDICT, was characterised by upregulation of cell-cycle related pathways and the downregulation of metabolism and cholesterol biosynthesis. The DESNT molecular subtype has distinct biological characteristics to those associated with the PREDICT model. We conclude that the inclusion of biological information alongside current clinical prognostic tools has the potential to improve the ability to choose the optimal treatment pathway for a patient.

Potential Role of Seven Proteomics Tissue Biomarkers for Diagnosis and Prognosis of Prostate Cancer in Urine.

As the currently available tests for the clinical management of prostate cancer (PCa) are still far from providing precise diagnosis and risk stratification, the identification of new molecular marker(s) remains a pertinent clinical need. Candidate PCa biomarkers from the published proteomic comparative studies of prostate tissue (2002-2020) were collected and systematically evaluated. AZGP1, MDH2, FABP5, ENO1, GSTP1, GSTM2, and EZR were chosen for further evaluation in the urine of 85 PCa patients and controls using ELISA. Statistically significant differences in protein levels between PCa and BPH showed FABP5 (p = 0.019) and ENO1 (p = 0.015). A biomarker panel based on the combination of FABP5, ENO1, and PSA provided the highest accuracy (AUC = 0.795) for PCa detection. The combination of FABP5, EZR, AZGP1, and MDH2 showed AUC = 0.889 in PCa prognosis, with 85.29% of the samples correctly classified into low and high Gleason score (GS) groups. The addition of PSA to the panel slightly increased the AUC to 0.914. AZGP1, FABP5, and EZR showed significant correlation with GS, stage, and percentage of positive biopsy cores. Although validation using larger patient cohorts will be necessary to establish the credibility of the proposed biomarker panels in a clinical context, this study opens a way for the further testing of more high-quality proteomics biomarkers, which could ultimately add value to the clinical management of PCa.

Biomarkers for the Detection and Risk Stratification of Aggressive Prostate Cancer.

Current strategies for the clinical management of prostate cancer are inadequate for a precise risk stratification between indolent and aggressive tumors. Recently developed tissue-based molecular biomarkers have refined the risk assessment of the disease. The characterization of tissue biopsy components and subsequent identification of relevant tissue-based molecular alterations have the potential to improve the clinical decision making and patient outcomes. However, tissue biopsies are invasive and spatially restricted due to tumor heterogeneity. Therefore, there is an urgent need for complementary diagnostic and prognostic options. Liquid biopsy approaches are minimally invasive with potential utility for the early detection, risk stratification, and monitoring of tumors. In this review, we focus on tissue and liquid biopsy biomarkers for early diagnosis and risk stratification of prostate cancer, including modifications on the genomic, epigenomic, transcriptomic, and proteomic levels. High-risk molecular alterations combined with orthogonal clinical parameters can improve the identification of aggressive tumors and increase patient survival.

Obesity-Related Cross-Talk between Prostate Cancer and Peripheral Fat: Potential Role of Exosomes.

Simple SummaryObesity is involved in many aspects of prostate cancer progression as a risk factor for prostate cancer, especially in the process of biochemical recurrence in the prostate. Approximately 27–53% of prostate cancer patients can develop biochemical recurrence after radical prostatectomy, which poses difficulties in the clinical management of prostate cancer, and this is closely related to the release of exosomes from adipose tissue in the obese state. In this review, we summarize the crosstalk between prostate cancer peripheral adiposity and prostate cancer and discuss the potential role of exosomes in this process and the prospects for the use of adipose exosomes. Exosomes play an important role in the crosstalk between the two this may be a new basis to explain obesity as a biochemical recurrence after prostate cancer surgery and a potential avenue for future prostate therapy.The molecular mechanisms of obesity-induced cancer progression have been extensively explored because of the significant increase in obesity and obesity-related diseases worldwide. Studies have shown that obesity is associated with certain features of prostate cancer. In particular, bioactive factors released from periprostatic adipose tissues mediate the bidirectional communication between periprostatic adipose tissue and prostate cancer. Moreover, recent studies have shown that extracellular vesicles have a role in the relationship between tumor peripheral adipose tissue and cancer progression. Therefore, it is necessary to investigate the feedback mechanisms between prostate cancer and periglandular adipose and the role of exosomes as mediators of signal exchange to understand obesity as a risk factor for prostate cancer. This review summarizes the two-way communication between prostate cancer and periglandular adipose and discusses the potential role of exosomes as a cross-talk and the prospect of using adipose tissue as a means to obtain exosomes in vitro. Therefore, this review may provide new directions for the treatment of obesity to suppress prostate cancer.

The Role of Curcumin in Prostate Cancer Cells and Derived Spheroids.

Simple SummaryIn recent years, considerable efforts have been made to discover new compounds useful for prostate cancer (PC) therapy and related clinical management. Promising advances in this field were reached with nutraceutical compounds. Curcumin represents an attractive therapeutic agent for mCRPC patients. Curcumin treatment displayed a dose-dependent reduction of DU145 and PC-3 PC cell viability similar to chemotherapeutic agents (paclitaxel, cisplatin, and docetaxel). Furthermore, by exploring the EGFR-mediated signaling, we observed that the treatment with both chemotherapeutic agents and curcumin reduced EGFR expression levels and ERK activation. Finally, we demonstrated that curcumin reduces the size of DU145 and PC-3 3D cell spheroids and has the potential to induce apoptosis.A major challenge in the clinical management of prostate cancer (PC) is to inhibit tumor growth and prevent metastatic spreading. In recent years, considerable efforts have been made to discover new compounds useful for PC therapy, and promising advances in this field were reached. Drugs currently used in PC therapy frequently induce resistance and PC progresses toward metastatic castration-resistant forms (mCRPC), making it virtually incurable. Curcumin, a commercially available nutritional supplement, represents an attractive therapeutic agent for mCRPC patients. In the present study, we compared the effects of chemotherapeutic drugs such as docetaxel, paclitaxel, and cisplatin, to curcumin, on two PC cell lines displaying a different metastatic potential: DU145 (moderate metastatic potential) and PC-3 (high metastatic potential). Our results revealed a dose-dependent reduction of DU145 and PC-3 cell viability upon treatment with curcumin similar to chemotherapeutic agents (paclitaxel, cisplatin, and docetaxel). Furthermore, we explored the EGFR-mediated signaling effects on ERK activation in DU145 and PC-3 cells. Our results showed that DU145 and PC-3 cells overexpress EGFR, and the treatment with chemotherapeutic agents or curcumin reduced EGFR expression levels and ERK activation. Finally, chemotherapeutic agents and curcumin reduced the size of DU145 and PC-3 spheroids and have the potential to induce apoptosis and also in Matrigel. In conclusion, despite different studies being carried out to identify the potential synergistic curcumin combinations with chemopreventive/therapeutic efficacy for inhibiting PC growth, the results show the ability of curcumin used alone, or in combinatorial approaches, to impair the size and the viability of PC-derived spheroids.

Abstract 5365: Repositioning nicardipine as a novel targeted therapy for chemoresistant prostate cancer

Abstract Background: It is imperative to develop novel therapeutics to overcome chemoresistance, a major obstacle in the clinical management of prostate cancer (PCa) and other cancers. Drug repositioning is being pursued as an attractive approach due to its potentially lower overall development costs and shorter timelines. The purpose of this study is to investigate the preclinical efficacy and mechanism of action of nicardipine, an FDA-approved hypertension drug, as a new treatment against chemoresistant prostate cancer. Methods: A panel of FDA-approved non-oncology drugs was screened for their selectivity and potency to inhibit chemoresistant PCa cells using a two-tier phenotypic screening platform (Theranostics, 2021, 11(14): 6873-6890). The mechanism of action of potential candidate(s) was evaluated using in silico docking, cellular and molecular assays in ARCaPE-shEPLIN and C4-2B-TaxR, two independent chemoresistant PCa cell lines. The in vivo efficacy was evaluated in clinically-relevant xenograft models of PCa. Results: Nicardipine exhibited high selectivity and potency against chemoresistant PCa cells via effectively inducing apoptosis and cell cycle arrest. The IC50 of nicardipine was determined as 0.5 μM and 2.1 μM in ARCaPE-shEPLIN and C4-2B-TaxR cells, respectively. Mechanically, nicardipine targeted a novel non-canonical enhancer of zeste homolog 2 (EZH2) signal pathway in chemoresistant PCa cells. Specifically, nicardipine might bind embryonic ectoderm development (EED), interrupt the integrity and stability of the polycomb repressive complex 2 (PRC2), reduce the phosphorylation and expression of EZH2, and subsequently inhibit downstream effectors including signal transducer and activator of transcription 3 (Stat3), S-phase kinase-associated protein 2 (SKP2), ATP binding cassette B1 (ABCB1) and survivin. In animal models, as a monotherapy, nicardipine significantly suppressed the intratibial growth of chemoresistant C4-2B-TaxR xenografts, with an average PSA level of 43.47 ng/ml, 36.63 ng/ml, and 28.78 ng/ml for the vehicle control, docetaxel, and nicardipine groups at the endpoint, respectively (p &amp;lt; 0.05 between the nicardipine group and the vehicle control or docetaxel groups). As a combination regime, nicardipine synergistically enhanced the efficacy of docetaxel against the intratibial growth of C4-2 xenografts, with an average PSA level of 79.17 ng/ml, 49.04 ng/ml, 42.80 ng/ml, and 23.23 ng/ml for the vehicle control, docetaxel, nicardipine, and combination groups at the endpoint, respectively (p &amp;lt; 0.0001 or 0.01 between the combination group and the vehicle control or docetaxel groups, respectively). Conclusion: These results demonstrated that, for the first time, nicardipine could be a novel EED inhibitor that has the potential to be promptly tested in PCa patients to overcome chemoresistance and improve clinical outcomes. Citation Format: Xin Li, Alira Danaher, Jason M. Wu, Yifei Wu, Zhong-Ru Xie, Nicholas Cook, Nathan Bowen, Daqing Wu. Repositioning nicardipine as a novel targeted therapy for chemoresistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5365.

Prostate Cancer Treatment: 177Lu-PSMA-617 Considerations, Concepts, and Limitations.

The phase III VISION trial using 177Lu-PSMA-617 has significant implications for the field of theranostics and broad repercussions for the clinical management of prostate cancer. Metastatic prostate cancer is a rapidly evolving field with a complex landscape that has multiple established therapies, including chemotherapies, hormonal therapies, immunotherapies, radiopharmaceuticals, and targeted therapies. The current landscape was created by an important series of pivotal phase III trials, typically with an overall-survival endpoint. To best understand the VISION trial (performed on patients with metastatic castration-resistant prostate cancer), it is essential to have a thorough understanding of the key decisions that underpinned the design, as well as the context of those decisions. Here, we describe critical elements of the VISION phase III trial and how those elements will shape regulatory decision making and clinic practice. Inclusion and exclusion criteria were carefully crafted, as were treatments, assessments, and endpoints. The results of the VISION trial were impressive, with clear improvements in survival for patients having few treatment alternatives. Besides the significant progress, there are also significant limitations. 177Lu-PSMA-617 treatments will have far-reaching implications for prostate cancer. Food and Drug Administration approval was granted March 23, 2022, on the basis of the VISION data.

Gremlin1 is a therapeutically targetable FGFR1 ligand that regulates lineage plasticity and castration resistance in prostate cancer.

Among the greatest hurdles in clinical management of prostate cancer (PCa) are the progression to lethal castration-resistant prostate cancer (CRPC) and the lack of suitable targeted therapies for advanced disease. Here we identify Gremlin1 as a ligand for fibroblast growth factor receptor 1 (FGFR1), which promotes lineage plasticity and drives castration resistance. Importantly, we generate a specific anti-Gremlin1 therapeutic antibody and demonstrate synergistic effect with androgen deprivation therapy (ADT) in CRPC. GREM1 transcription is suppressed by androgen receptor (AR) and released following ADT. We show that Gremlin1 binds to FGFR1 and activates downstream MAPK signaling. Gremlin1 interacts with FGFR1 differently to its canonical ligand FGF1, as revealed through protein structure docking and mutagenesis experiments. Altogether, our data indicate Gremlin1 as a promising candidate therapeutic target for CRPC.