Search Results (938)

Background: Although the relationship between androgen deprivation therapy (ADT) for prostate cancer (PC) and the biological mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unequivocally unclear, it is possible that exposure to the virus may influence PC evolution by altering TMPRSS2 expression. This study aims to evaluate the long-term oncological outcomes of patients with metastatic PC who were undergoing medical therapy at the time of contracting SARS-CoV-2 and who resumed/continued anticancer treatment after recovery. Methods: We retrospectively evaluated a consecutive series of 151 metastatic PC patients who developed SARS-CoV-2 infection while receiving one active systemic anticancer therapy (125 metastatic castration-resistant PC (mCRPC) patients and 26 metastatic hormone-sensitive PC (mHSPC) patients). We evaluated variables that influence the ability to maintain or resume the ongoing therapy. For the maintained/resumed therapies, we calculated the post-infection overall survival (piOS) and the overall survival (OS). Results: Of the patients, 12.6% died due to SARS-CoV-2 infection, 10.6% recovered from the infection but failed to maintain/resume the ongoing anticancer treatment, and the remaining 76.8% maintained/resumed the treatment after recovery. Hospitalization, duration of infection, and the type of ongoing anticancer agent influenced these treatment changes. In the cohort of mCRPC patients, the median piOS was 32 months, and the median OS was 67.8 months. The median piOS was not achieved in the cohort of mHSPC patients, while the median OS was 122 months. The outcomes of single anticancer agents were in line with those of pivotal trials. Conclusions: Although observed in a highly selected population of PC patients who survived SARS-CoV-2 infection and were able to resume/maintain anticancer therapy, the survival outcomes of this study appear to be in line with those reported in pivotal studies, and SARS-CoV-2 infection does not seem to have adversely affected long-term oncological outcomes. Full article

Prostate cancer is one of the most common malignancies in men, and advanced or metastatic disease remains associated with substantial morbidity and mortality. Therapeutic progress in recent years has been driven by the introduction of targeted treatment strategies, notably poly (ADP-ribose) polymerase (PARP) inhibitors, prostate-specific membrane antigen (PSMA)–directed radioligand therapy (RLT), and androgen receptor pathway inhibitors (ARPIs). This review summarizes evidence from phase II and III clinical trials, meta-analyses, and real-world studies evaluating the efficacy, safety, and clinical integration of olaparib, lutetium (¹⁷⁷Lu) vipivotide tetraxetan, and abiraterone in advanced prostate cancer. Emphasis is placed on the practical clinical application of these agents, including patient selection, treatment sequencing, and combination strategies. PARP inhibition with olaparib has demonstrated clear benefits in metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) mutations, particularly BRCA1/2 alterations. PSMA-directed RLT offers a survival advantage in PSMA-positive mCRPC following AR pathway inhibition, with distinct toxicity considerations that influence patient selection. Abiraterone remains a cornerstone therapy across disease stages and plays an important role both as monotherapy and as a combination partner. Emerging data suggest a potential synergy between PARP inhibitors and AR-targeted agents, while also highlighting the limitations of biomarker-unselected approaches. We conclude that the optimal use of PARP inhibitors, PSMA-targeted RLT, and ARPIs requires a personalized strategy guided by molecular profiling, functional imaging, prior treatment exposure, and safety considerations. This clinically focused overview aims to support evidence-based decision-making in an increasingly complex treatment landscape. Full article

Prostate cancer (PCa) is the leading cause of cancer-related deaths worldwide and the second most common cancer among men. Treatment options depend on factors like age, androgen sensitivity, PSA levels, Gleason score, TNM stage, and recurrence risk. Available treatments include hormonal therapy, radiation, surgery, and chemotherapy. Early immunological treatments were limited by poor lymphocyte infiltration and an immunosuppressive environment. Today, strategies such as dendritic cell vaccines, immune checkpoint inhibitors (ICIs), and adoptive cell therapy (ACT) are used. ACT, especially CAR T-cell strategies, aims to overcome traditional treatment limitations, particularly in advanced and metastatic castration-resistant prostate cancer (mCRPC), though it remains in early development. Personalized medicine uses molecular insights from the diseased tissue to tailor treatments. Variability in patient response, due to tumor heterogeneity and prior treatments, highlights the importance of personalized and combination therapies as future strategies for effective immunotherapy. This review explores the current landscape of PCa. We analyze treatment guidelines established by NCCN and EANM-ESTRO-ESUR-ISUP-SIOG. We comprehensively examine immunotherapeutic strategies currently available or under investigation for prostate cancer, with particular emphasis on ICIs, ACT with a focus on CAR T-cell therapy, combination approaches and therapeutic synergies, and predictive biomarkers of immunotherapy response. Additionally, we discuss the challenges and future directions in the implementation of immunotherapy for the management of prostate cancer. Full article

Prostate cancer remains one of the most common malignancies in men worldwide, with incidence and mortality steadily increasing across diverse populations. While early detection and radical prostatectomy can achieve durable control in a subset of patients, approximately 40% of men will ultimately experience biochemical recurrence often in the absence of clinically detectable disease. Conventional imaging approaches—CT, MRI, and bone scintigraphy—have limited sensitivity for early relapses, frequently leading to delayed diagnosis and suboptimal treatment planning. The discovery of prostate-specific membrane antigen (PSMA) in 1987 and its subsequent clinical translation into positron emission tomography (PET) imaging with [⁶⁸Ga]Ga-PSMA-11 in 2012, followed by U.S. FDA approval in 2020, has transformed the landscape of prostate cancer imaging. PSMA PET has demonstrated superior accuracy over conventional imaging, as highlighted in the landmark proPSMA trial and now serves as the foundation for theranostic approaches that integrate diagnostic imaging with targeted radioligand therapy. The clinical approval of [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto^®: (lutetium Lu 177 vipivotide tetraxetan, Advanced Accelerator Applications USA, Inc., a Novartis company) has established targeted radioligand therapy as a viable option for men with metastatic castration-resistant prostate cancer, extending survival in patients with limited alternatives. Emerging strategies, including next-generation ligands with improved tumor uptake and altered clearance pathways, as well as the integration of artificial intelligence for imaging quantification, are poised to further refine patient selection, dosimetry, and treatment outcomes. This review highlights the evolution of PSMA-based imaging and therapy, discusses current clinical applications and limitations, and outlines future directions for optimizing theranostic strategies in prostate cancer care. Full article

Background/Objectives: Docetaxel is a widely used chemotherapeutic agent for several malignancies and is an established treatment for castration-resistant prostate cancer. However, its poor aqueous solubility, systemic toxicity, and the emergence of drug resistance limit its clinical benefit. Zein, a prolamin, forms micelles that enhance the solubility and delivery of hydrophobic drugs. As PEG length and ligand presentation govern micelle behavior, we investigated transferrin-functionalized PEGylated zein micelles as docetaxel nanocarriers and examined how PEG chain length (5 K vs. 10 K) and transferrin-mediated targeting affect delivery to prostate cancer cells. Methods: Docetaxel-loaded zein micelles bearing 5 K or 10 K PEG chains were prepared and conjugated to transferrin. Formulations were characterized for size, charge, morphology, critical micelle concentration, colloidal stability, drug loading and transferrin density. Cellular uptake and mechanisms were assessed in PC-3-Luc, DU145 and LNCaP cells by confocal microscopy, flow cytometry and pharmacological inhibition. Anti-proliferative activity was determined by MTT assays. Results: Both PEG5K and PEG10K micelles formed micellar dispersions with low polydispersity and high encapsulation efficiency. PEG5K micelles achieved higher transferrin conjugation and drug loading. Transferrin-functionalized PEG5K micelles showed enhanced uptake in DU145 and LNCaP cells but lower internalization in PC-3-Luc cells. Inhibitor studies indicated receptor-dependent uptake via clathrin- and caveolae-mediated endocytosis. Free docetaxel remained the most potent. However, among nanocarriers, transferrin-targeted PEG5K micelles showed the greatest anti-proliferative efficacy relative to their non-targeted counterparts, whereas transferrin-targeted PEG10K micelles were less potent than the non-targeted PEG10K micelles across all three cell lines. Conclusions: PEG chain length and ligand presentation are key determinants of uptake and cytotoxicity of docetaxel-loaded zein micelles. Shorter PEG chains favor effective transferrin display and receptor engagement, whereas longer PEG likely induces steric hindrance and reduces targeting, supporting transferrin-conjugated PEG5K zein micelles (the lead formulation in this study) as a targeted delivery platform that improves performance relative to matched non-targeted micelles in vitro, while free docetaxel remains more potent in 2D monolayer assays. Full article

Prostate cancer (PCa) is a common malignancy in men worldwide, with incidence projected to rise in the coming years. Traditional screening and diagnostic methods, such as prostate-specific antigen (PSA) testing and biopsy, face limitations in specificity and invasiveness. Circulating microRNAs (miRNAs) have emerged as stable, non-invasive biomarkers obtainable via liquid biopsies (blood, urine, semen) that could transform PCa management. These small regulatory RNAs reflect underlying tumor biology and are detectable at early disease stages, enabling improved early detection when used alongside or in place of PSA. Distinct miRNA expression patterns correlate with tumor aggressiveness. For example, miR-141 and miR-375 are elevated in metastatic cases, whereas let-7 family members and miR-326 are upregulated in aggressive disease, highlighting their prognostic value. Moreover, dynamic changes in reported miRNAs during therapy provide real-time insights into treatment response. In androgen-deprivation therapy (ADT), oncogenic miRNAs, such as miR-21 and miR-125b, increase upon resistance, whereas a decline in tumor-suppressive miRNAs, such as miR-23b/-27b, flags the transition to castration-resistant PCa (CRPC). Similarly, baseline levels of miRNAs (e.g., miR-200b/c, miR-20a) can predict chemotherapy outcomes. Integrating multi-miRNA panels has demonstrated superior accuracy for risk stratification and monitoring, paving the way for personalized treatment. Although promising, clinical implementation of miRNA-based assays requires further validation, standardization of protocols, and large-scale prospective studies. Harnessing circulating miRNAs could usher in a new era of precision oncology for PCa, improving early diagnosis, prognostication, and real-time therapeutic guidance. Full article

Advanced prostate cancer, particularly castration-resistant disease, remains challenging to treat due to intratumoral heterogeneity, immune exclusion, and a suppressive tumor microenvironment. Within this ecosystem, cancer-associated fibroblasts shape tumor–stroma communication, but their marked heterogeneity and plasticity complicate classification and make indiscriminate fibroblast depletion potentially ineffective or even harmful. This review summarizes recent progress in fibroblast origins, functional subtypes, and fibroblast-driven mechanisms that promote tumor progression and therapy resistance, as well as emerging therapeutic opportunities in prostate cancer. We conducted a structured literature search of PubMed, ScienceDirect, and major publisher platforms (including Nature and SpringerLink) from database inception to 15 February 2025, supplemented by targeted manual screening of reference lists. Evidence from single-cell/spatial-omics and mechanistic studies indicates that prostate tumors contain multiple fibroblast programs that occupy distinct niches yet can interconvert. Across these studies, it was found that these fibroblasts contribute to immune suppression, extracellular matrix remodeling and stromal barrier formation, angiogenesis, and metabolic support, collectively limiting drug penetration and reinforcing immune evasion; therapeutic pressure can further rewire fibroblast states and resistance-associated signaling. Overall, the literature supports a shift toward function- and subtype-directed intervention rather than “one-size-fits-all” targeting, with promising directions including precision targeting and reversible reprogramming, rational combination strategies, and localized delivery approaches that reduce stromal barriers while preserving tissue homeostasis in high-risk and treatment-refractory prostate cancer. Full article

Disease heterogeneity across a diverse patient cohort poses challenges to cancer drug development due to inter-patient variability in treatment responses. However, current preclinical models fail to depict inter-patient tumor heterogeneity, leading to a high failure rate when translating preclinical leads into clinical successes. We integrated the expression profiles of prostate cancer (PC) lines and castration-resistant PC (CRPC) patient tumors to identify cell-lines that transcriptomically match distinct tumor subtypes in a clinical cohort. Representative cell-lines were co-cultured to create “mixed-cell” models depicting inter-patient heterogeneity in CRPC, which were employed to assess drug combinations. When drug combinations previously tested in CRPC clinical cohorts were assessed to establish proof of concept, in vitro responses measured in our models concurred with their known clinical efficacy. Additionally, novel drug combinations computationally predicted to be efficacious in heterogeneous tumors were evaluated. They demonstrated preclinical efficacy in the mixed-cell models, suggesting they will likely benefit heterogeneous patient cohorts. Furthermore, we showed that the current practice of screening cell-lines/xenografts separately and aggregating their responses, failed to detect their efficacy. We believe that the application of our models will enhance the accuracy of preclinical drug assessment, thereby improving the success rate of subsequent clinical trials. Full article

Prostate cancer remains a leading cause of cancer-related mortality and castration-resistant prostate cancer (CRPC) is a critical therapeutic challenge. This review establishes a conceptual framework analyzing ferroptosis vulnerability through two principles: “robustness through redundancy” in defense systems and the “evolutionary arms race” between androgen receptor (AR) signaling and oxidative resistance. We traced the evolutionary trajectory of hormone-sensitive diseases, where the AR coordinates ferroptosis defenses via SLC7A11, MBOAT2, and PEX10 regulation through progressive adaptations: AR-V7 splice variants that maintain defense independently of androgens, AR amplification conferring hypersensitivity, and AR-independent JMJD6-ATF4 bypass in SPOP-mutated tumors. This transforms ferroptosis from a static vulnerability to a stage-specific strategy. Novel approaches include menadione-based VPS34 targeting, which induces triaptosis through an oxidative endosomal catastrophe. We categorized the rational combinations mechanistically as vertical inhibition (multi-step targeting of single pathways), horizontal inhibition (synthetic lethality across parallel defenses), and vulnerability induction (creating exploitable dependencies). Ferroptosis-induced immunogenic cell death enables synergy with checkpoint inhibitors, potentially transforming immunologically “cold” prostate tumors. This review establishes ferroptosis targeting as a precision medicine paradigm exploiting the tension between the oxidative requirements of cancer cells and their evolved, yet architecturally vulnerable, defense systems, providing a framework for stage-specific, biomarker-guided interventions. Full article

Prostate cancer (PCa) is the second most prevalent cancer among men and a major cause of cancer-related mortality worldwide. Despite an initial favorable response to hormone-based therapies, many patients ultimately develop an advanced and lethal form of the disease, referred to as castration-resistant PCa (CRPC). CRPC is associated with poor prognosis and a lack of effective curative treatments. As a result, new alternatives or improved therapeutic strategies to combat this life-threatening condition are urgently needed. Chalcones, also referred to as 1,3-diphenyl-2-propen-1-ones, have attracted significant attention because of their potent antitumor properties. Owing to their distinctive chemical structure and diverse biological activities, these compounds are promising candidates for treating various cancers, including PCa. Both naturally occurring and synthetically derived chalcones have demonstrated anticancer potential by modulating key cellular processes, including apoptosis, cell cycle regulation, cell migration, invasion, metastasis and angiogenesis, as well as major signaling pathways, such as PI3K/Akt/mTOR, androgen signaling, and NF-κB. This review aims to outline the recent advances in the therapeutic potential of chalcone derivatives in prostate cancer, with a focus on their molecular targets, mechanisms of action, and translational relevance. Full article

Background/Objectives: Accurate absorbed dose estimation is essential for optimising targeted radionuclide therapy (TRT) in metastatic castration-resistant prostate cancer, where kidney toxicity is dose-limiting. [¹⁷⁷Lu]Lu-rhPSMA-10.1 is a novel PSMA-targeted radioligand with favourable tumour-to-kidney uptake ratios; however, inter-patient pharmacokinetic variability can lead to differences in organ and tumour absorbed doses under fixed-activity administration. Personalised dosimetry offers a means to address this variability. This work aims to create mouse PBPK model-based digital twins for [¹⁷⁷Lu]Lu-rhPSMA-10.1 to test the model’s resistance to noise and evaluate its impact on accuracy and absorbed dose calculations. Methods: Five CB-17 SCID mice bearing LNCaP tumour xenografts received 2.6–3.1 MBq [¹⁷⁷Lu]Lu-rhPSMA-10.1 intravenously. Biodistribution was assessed 24 h post-injection by organ weighing and gamma counting. The PBPK model, implemented in MATLAB SimBiology (R2023a), was fitted to individual biodistribution data using mouse-specific physiological parameters. Digital twins—combining the model with fitted parameters—were used to generate time–activity curves (TACs) for kidneys, tumours, and the whole body. Gaussian noise ($\sigma$ = 0–0.35) was added to TACs to simulate measurement error. The model was refitted, and absorbed doses from time-integrated activities (TIAs) were compared to digital twin references. Results: The digital twin approach reproduced experimental data with physiologically plausible parameters. Absorbed dose estimates remained consistent and robust, deviating by <2.3% in kidneys and <1.0% in tumours. Conclusions: PBPK-based digital twins enable reliable, individualised dosimetry, even under substantial measurement uncertainty. Full article

Circulating tumor DNA (ctDNA) analysis has emerged as a powerful and minimally invasive approach for genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), enabling real-time detection of tumor-derived mutations that guide therapy. Approximately 20% of mCRPC patients harbor alterations in homologous recombination repair (HRR) genes, most commonly BRCA1/2 and ATM, which are actionable with different poly-(ADP-ribose) polymerase inhibitors (PARPIs) used as monotherapy or in combination with androgen receptor signaling inhibitors (ARSIs). A smaller subset of patients with mismatch repair deficiency (MMRd) or microsatellite instability-high (MSI-high) tumors may benefit from immune checkpoint blockade with pembrolizumab. Different FDA-approved liquid biopsy assays detect these actionable alterations when tissue biopsies are unavailable or insufficient. This review summarizes current evidence on ctDNA-based genotyping in mCRPC, highlighting clinically actionable mutations, corresponding targeted therapies, and technical and analytical considerations for clinical implementation. By capturing DNA shed from multiple metastatic sites, ctDNA profiling provides a comprehensive view of tumor heterogeneity and enables serial monitoring of molecular evolution. Overall, ctDNA analysis represents a transformative advance in precision oncology, supporting personalized treatment selection and ongoing assessment of therapeutic response in mCRPC. Full article

Castration-resistant prostate cancer presents radiotherapeutic challenges, especially in optimizing the cytosolic internalization of therapeutic radiopharmaceuticals. This research aimed to design and evaluate in vitro, a new dimeric radiopharmaceutical, [¹⁷⁷Lu]Lu–iPSMA–iGRP78, which combines PSMA and GRP78 inhibitors in a heterodimeric radioligand to improve the radionuclide internalization and cytotoxicity efficacy. Molecular docking showed that the dimer iPSMA–iGRP78 presents a higher affinity for GRP78 (CNN-docking score: −14.0 kcal·mol⁻¹, pKi: 10) and for PSMA (CNN-docking score: −17.0 kcal·mol⁻¹, pKi: 11.5) compared to the monomers iGRP78 (CNN-docking score: −11.0 kcal·mol⁻¹, pKi: 9.4) and iPSMA (CNN-docking score: −13.9 kcal·mol⁻¹, pKi: 10.2). The saturation binding assay using LNCaP cells (PSMA+, CS-GRP78+) showed an affinity (K_d) of 1.883 nM for [¹⁷⁷Lu]Lu–iPSMA–iGRP78 and 2.245 nM for [¹⁷⁷Lu]Lu–iPSMA. The dimeric radiopharmaceutical achieved 10.44 ± 2.43% cytosolic internalization and 4.81 ± 0.94% nuclear internalization, while the [¹⁷⁷Lu]Lu–iPSMA monomer showed 6.45 ± 0.60% cytosolic internalization and no uptake in the cell nucleus. In PC3 cells (PSMA–, CS-GRP78–), [¹⁷⁷Lu]Lu–iPSMA–iGRP78 uptake was negligible, demonstrating specificity. Treatment with the dimeric radiopharmaceutical reduced cell viability (69.93 ± 4.85% of dead cells) significantly more than [¹⁷⁷Lu]Lu–iPSMA (38.63 ± 6.13% of dead cells). In conclusion, conjugation of a GRP78 inhibitor to [¹⁷⁷Lu]Lu–iPSMA improves the radionuclide internalization and cytotoxicity in prostate cancer cells, suggesting that the bispecific radiopharmaceutical is a promising strategy in prostate cancer treatment. Full article

Prostate cancer (PCa) remains one of the most prevalent malignancies among men worldwide and continues to pose significant therapeutic challenges, especially in its metastatic and castration-resistant forms. Over the past two decades, the treatment paradigm has evolved from monotherapy with androgen deprivation therapy (ADT) to a multifaceted approach integrating chemotherapy, androgen receptor axis-targeted therapies (ARATs), radiopharmaceuticals, and precision medicine. This review explores the molecular underpinnings of PCa, including genetic and epigenetic alterations such as BRCA1/2, TP53, and PTEN mutations, and their role in disease progression and treatment resistance. We detail the evidence supporting the integration of systemic agents like abiraterone, enzalutamide, and darolutamide into both hormone-sensitive and castration-resistant settings. Furthermore, we highlight the expanding role of radioligand therapies, including radium-223 and Lutetium-177-labeled PSMA-617 (Lu-PSMA-617), as well as the growing impact of PARP inhibitors in genomically selected patients. The emergence of theranostic strategies and next-generation sequencing has paved the way for personalized treatment algorithms, moving toward a truly precision oncology model in PCa. This comprehensive review synthesizes current therapeutic strategies, clinical trial evidence, and future directions aimed at optimizing outcomes and quality of life for patients with advanced prostate cancer. Full article

Castration-resistant prostate cancer (CRPC) remains a major clinical challenge, with disease progression frequently occurring despite the use of potent androgen receptor (AR)-targeted therapies. As AR signalling continues to drive tumour growth in this setting, new therapeutic strategies are being developed to disrupt the AR axis through both direct and indirect mechanisms. This review highlights a selection of promising agents in preclinical or clinical development that represent the next generation of therapies targeting AR signalling. Direct approaches include novel agents that degrade the AR or target domains beyond the conventional ligand-binding domain, aiming to overcome resistance to existing anti-androgens. Indirect strategies are designed to interfere with AR function by modulating AR-associated transcriptional co-regulators, chromatin accessibility, and other regulatory proteins, such as splicing factors, that are critical for sustaining AR-driven gene expression in prostate cancer. Together, these therapies form the basis of emerging strategies to more effectively suppress AR activity in CRPC. This review discusses AR-activating mechanisms, the mechanisms of action of these agents, their clinical development status, and their potential to reshape future treatment paradigms in CRPC. Full article