Search Results (970)

Background: The involvement of the intratumoral microbiome in prostate cancer progression is becoming increasingly acknowledged. This study analyzed the microbiome of prostate cancer tissues from patients with localized prostate cancer (LPC, stages 1–2) and advanced prostate cancer (APC, stages 3–4) to determine its association with cancer progression. Methods: Paraffin-embedded tissue samples obtained during radical prostatectomy underwent 16S rRNA amplicon-based profiling. Results: The profile of the bacterial communities in LPC and APC differed remarkably. While species diversity remained stable, species richness (as determined by the ACE analysis) was significantly lower in APC, correlating with a decrease in Enhydrobacter (which is more abundant in LPC) and an increase in Lautropia (enriched in APC). The role of Lautropia in the progression of cancer was confirmed by in vitro studies employing cell lines from prostate cancer. Conclusions: These findings demonstrate the potential of microbiome-targeted interventions in the management of prostate cancer. Full article

In today’s oncology, immunotherapy arises as a potent complement for conventional cancer treatment, allowing for obtaining better patient outcomes. B7-H3 (CD276) is a member of the B7 protein family, which emerged as an attractive target for the treatment of various tumors. The molecule modulates anti-cancer immune responses, acting through diverse signaling pathways and cell populations. It has been implicated in the pathogenesis of numerous malignancies, including melanoma, gliomas, lung cancer, gynecological cancers, renal cancer, gastrointestinal tumors, and others, fostering the immunosuppressive environment and marking worse prognosis for the patients. B7-H3 targeting therapies, such as monoclonal antibodies, antibody–drug conjugates, and CAR T-cells, present promising results in preclinical studies and are the subject of ongoing clinical trials. CAR-T therapies against B7-H3 have demonstrated utility in malignancies such as melanoma, glioblastoma, prostate cancer, and RCC. Moreover, ADCs targeting B7-H3 exerted cytotoxic effects on glioblastoma, neuroblastoma cells, prostate cancer, and craniopharyngioma models. B7-H3-targeting also delivers promising results in combined therapies, enhancing the response to other immune checkpoint inhibitors and giving hope for the development of approaches with minimized adverse effects. However, the strategies of B7-H3 blocking deliver substantial challenges, such as poorly understood molecular mechanisms behind B7-H3 protumor properties or therapy toxicity. In this review, we discuss B7-H3’s role in modulating immune responses, its significance for various malignancies, and clinical trials evaluating anti-B7-H3 immunotherapeutic strategies, focusing on the clinical potential of the molecule. Full article

Albumin-binding agents enhance tumor uptake of radiopharmaceuticals targeting prostate-specific membrane antigens (PSMAs) in radiotherapy. We synthesized PSMA-NARI-56, a molecule with both PSMA targeting activity and albumin-binding moiety, labeled with ¹⁷⁷Lu as the therapeutic agent. The aim of this study was to determine the specific binding of ¹⁷⁷Lu-PSMA-NARI-56 towards PSMA, assess its biodistribution, and evaluate therapeutic effectiveness by tumor-bearing mice. The effect of ¹⁷⁷Lu-PSMA-NARI-56 viability of PSMA-positive cell (LNCaP) was evaluated. Biodistribution and endoradiotherapy studies were utilized to determine the distribution, targeting, and anti-tumor efficacy by tumor-bearing mice identified by ¹¹¹In-PSMA-NARI-56. ¹⁷⁷Lu-PSMA-NARI-56 exhibited a significant impact on the viability of the LNCaP cell. Biodistribution results revealed the maximum tumor uptake of ¹⁷⁷Lu-PSMA-NARI-56 occurring within 24 h, reaching 40.56 ± 10.01%ID/g. In radionuclide therapy, at 58 days post-injection (p.i.), ¹⁷⁷Lu-PSMA-NARI-56 demonstrated superior tumor inhibition (98%) compared to ¹⁷⁷Lu-PSMA-617 (58%), and the mouse survival rate after 90 days of radiotherapy (90%) was also higher than that of ¹⁷⁷Lu-PSMA-617 (30%) in LNCaP tumor-bearing mice. In the PSMA-positive animal model, ¹⁷⁷Lu-PSMA-NARI-56 shows higher potential radiotheranostic and prolonged accumulation (identify by ¹¹¹In-PSMA-NARI-56/nanoSPECT/CT image), offering the potential for improved treatment effectiveness and increased survival rates when compared to ¹⁷⁷Lu-PSMA-617. Full article

Background/Objectives: Androgen deprivation therapy (ADT) is the mainstay of prostate cancer treatment, especially in advanced disease. In particular, the gonadotropin-releasing hormone agonists (aGnRH) reduce the production of gonadotropin and, therefore, of testosterone. In about 10% of patients, the non-pulsatile stimulation of GnRH receptor initially causes a surge in LH and testosterone, defined as the “flare-up phenomenon”, leading to increased bone pain, spinal cord compression, bladder outlet obstruction and cardiovascular issues. To mitigate this effect, combining a first-generation antiandrogen agent (FGA) with aGnRH is recommended. However, second-generation anti-androgens, such as apalutamide, bind selectively and irreversibly to the androgen receptor (AR), exhibiting a more efficient inhibition of the AR pathway. Methods: This is a descriptive retrospective study of 27 patients (pts) with mHSPC, treated at a single center (“Santa Maria delle Grazie” Hospital in Pozzuoli, ASL Napoli 2 Nord, Italy) between June 2022 and April 2024. Patients received apalutamide monotherapy for 14 days followed by continuous combination with aGnRH plus apalutamide. Serum PSA and testosterone levels were measured at baseline, at day 14 (after 13 days of apalutamide monotherapy), at day 28 (after an additional 15 days of apalutamide plus a aGnRH), and at day 60. Results: PSA levels decreased from a mean of 45.2 (±63.1) ng/mL at baseline to a mean of 12.6 (±23.4) ng/mL at day 14 and to 3.3 ng/mL (±6.0) at day 28 of treatment. After 14 days of apalutamide monotherapy, 21 patients (77.8%) achieved a >50% PSA reduction and 4 (14.8%) a >90% PSA reduction. The number of patients with undetectable PSA was one (3.7%) at day 14, two (7.4%) at day 28, and nine (33.3%) at day 60. The mean serum testosterone levels were 6.56 (±4.46) ng/mL at baseline, 6.58 (±4.42) ng/mL at day 14, and 2.40 (± 3.38) ng/mL at day 28. No significant difference in PSA and testosterone level reduction during treatment emerged between subgroups of patients with low- vs. high-volume disease. Conclusions: Apalutamide alone is a viable option for mitigating the flare-up phenomenon, avoiding first generation anti-androgen therapy, and it can achieve rapid and deep biochemical control. Full article

Bone is the most frequent site of distant metastasis in advanced prostate cancer (PCa), contributing substantially to patient morbidity and mortality. Hypoxia, a defining feature of the solid tumour microenvironment, plays a pivotal role in driving bone-tropic progression by promoting epithelial-to-mesenchymal transition (EMT), cancer stemness, extracellular matrix (ECM) remodelling, and activation of key signalling pathways such as Wingless/Integrated (Wnt) Wnt/β-catenin and PI3K/Akt. Hypoxia also enhances the secretion of extracellular vesicles (EVs), enriched with pro-metastatic cargos, and upregulates bone-homing molecules including CXCR4, integrins, and PIM kinases, fostering pre-metastatic niche formation and skeletal colonisation. In this review, we analysed current evidence on how hypoxia orchestrates PCa dissemination to bone, focusing on the molecular crosstalk between HIF signalling, Wnt activation, EV-mediated communication, and cellular plasticity. We further explore therapeutic strategies targeting hypoxia-related pathways, such as HIF inhibitors, hypoxia-activated prodrugs, and Wnt antagonists, with an emphasis on overcoming therapy resistance in castration-resistant PCa (CRPC). By examining the mechanistic underpinnings of hypoxia-driven bone metastasis, we highlight promising translational avenues for improving patient outcomes in advanced PCa. Full article

Bone metastasis remains a significant cause of morbidity and diminished quality of life in patients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 and RASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to cancer cell plasticity and facilitates epithelial-to-mesenchymal transition (EMT). Key histone modifiers, including KLF5, EZH2, and the demethylases KDM4/6, regulate osteoclastogenic signaling pathways and the transition between metastatic dormancy and reactivation. Simultaneously, SWI/SNF chromatin remodelers such as BRG1 and BRM reconfigure enhancer–promoter interactions that promote bone tropism. Non-coding RNAs, including miRNAs, lncRNAs, and circRNAs (e.g., miR-34a, NORAD, circIKBKB), circulate via exosomes to modulate the RANKL/OPG axis, thereby conditioning the bone microenvironment and fostering the formation of a pre-metastatic niche. These mechanistic insights have accelerated the development of epigenetic therapies. DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling. Inhibitors targeting EZH2, BET proteins, and KDM1A are now advancing through early-phase clinical trials, often in combination with bisphosphonates or immune checkpoint inhibitors. Moreover, novel approaches such as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies offer locus-specific reprogramming potential. Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases. Full article

Targeted radioligand therapy (RLT) is an emerging field in anticancer therapeutics with great potential across tumor types and stages of disease. While much progress has focused on agents targeting somatostatin receptors and prostate-specific membrane antigen (PSMA), the same advanced radioconjugation methods and molecular targeting have spurred the development of numerous theranostic combinations for other targets. A number of the most promising agents have progressed to clinical trials and are poised to change the landscape of positron emission tomography (PET) imaging. Here, we present recent data on some of the most important emerging molecular targeted agents with their exemplar clinical images, including agents targeting fibroblast activation protein (FAP), hypoxia markers, gastrin-releasing peptide receptors (GRPrs), and integrins. These radiopharmaceuticals share the promising characteristic of being able to image multiple types of cancer. Early clinical trials have already demonstrated superiority to ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) for some, suggesting the potential to supplant this longstanding PET radiotracer. Here, we provide a primer for practicing radiologists, particularly nuclear medicine clinicians, to understand novel PET imaging agents and their clinical applications, as well as the availability of companion targeted radiotherapeutics, the status of their regulatory approval, the potential challenges associated with their use, and the future opportunities and perspectives. Full article

Targeted radionuclide therapy (TRT) utilizes radiopharmaceuticals to deliver radiation directly to cancer cells while sparing healthy tissues. Beyond the absorbed dose of ablative radiation, TRT induces non-targeted effects (NTEs) that significantly enhance its therapeutic efficacy. These effects include radiation-induced bystander effects (RIBEs), abscopal effects (AEs), radiation-induced genomic instability (RIGI), and adaptive responses, which collectively influence the behavior of cancer cells and the tumor microenvironment (TME). TRT also modulates immune responses, promoting immune-mediated cell death and enhancing the efficacy of combination therapies, such as the use of immune checkpoint inhibitors. The molecular mechanisms underlying TRT involve DNA damage, oxidative stress, and apoptosis, with repair pathways like homologous recombination (HR) and non-homologous end joining (NHEJ) playing critical roles. However, challenges such as tumor heterogeneity, hypoxia, and radioresistance limit the effectiveness of this approach. Advances in theranostics, which integrate diagnostic imaging with TRT, have enabled personalized treatment approaches, while artificial intelligence and improved dosimetry offer potential for treatment optimization. Despite the significant survival benefits of TRT in prostate cancer and neuroendocrine tumors, 30–40% of patients remain unresponsive, which highlights the need for further research into molecular pathways, long-term effects, and combined therapies. This review outlines the dual mechanisms of TRT, direct toxicity and NTEs, and discusses strategies to enhance its efficacy and expand its use in oncology. Full article

Background/Objectives: Prostate cancer (PCa) is diagnosed at an earlier median age, more advanced stage, and has worse clinical outcomes in African American (AA) men compared to European Americans (EA). Methods: To investigate the role of aberrant DNA methylation in tumor-adjacent stroma (TAS), methyl binding domain sequencing (MBD-seq) was performed on AA (n = 17) and EA (n = 15) PCa patients. This was independently confirmed using the long interspersed nuclear element-1 (LINE-1) assay. Pathway analysis was performed on statistically significantly differentially methylated genes for AA and EA TAS. DNA methylation profiles of primary cultured AA and EA carcinoma-associated fibroblasts (CAFs) were compared with AA and EA TAS. AA and EA CAFs were treated with demethylating agent 5-Azacytidine (5-AzaC). Results: AA TAS exhibited higher global DNA methylation than EA TAS (p-value < 0.001). Of the 3268 differentially methylated regions identified (DMRs, p-value < 0.05), 85% (2787 DMRs) showed increased DNA methylation in AA TAS, comprising 1648 genes, of which 1379 were protein-coding genes. Based on DNA methylation levels, two AA subgroups were identified. Notably, AA patients with higher DNA methylation were predominantly those with higher Gleason scores. Pathway analysis linked methylated genes in AA TAS to several key signaling pathways (p-value < 0.05), including immune response (e.g., IL-1, IL-15, IL-7, IL-8, IL-3, and chemokine), Wnt/β-catenin, androgen, PTEN, p53, TGF-β, and circadian clock regulation. A total of 168 concordantly methylated genes were identified, with 109 genes (65%) showing increased methylation in AA CAFs and TAS (p-value < 0.05). Treatment with 5-AzaC significantly reduced DNA methylation of concordant genes in AA CAFs (p-value < 0.001). Conclusions: These findings suggest a distinct stromal methylome in AA, providing a foundation for integrating demethylating agents into standard therapies. This approach targets the tumor microenvironment, potentially addressing PCa disparities in AA men. Full article

BRCA1 and BRCA2 are associated with advanced prostate cancer progression and poor prognosis. Copy number variants (CNVs) of these genes play a crucial role in guiding targeted treatments, particularly for patients receiving PARP inhibitors. However, CNV detection using multiplex ligation-dependent probe amplification (MLPA) is often limited by tumor heterogeneity, leading to ambiguous results. This study therefore aimed to evaluate BRCA1/2 CNVs in advanced prostate cancer patients using droplet digital PCR (ddPCR) and compare the results with MLPA. DNA from 11 advanced prostate cancer tissues was analyzed using both methods, in parallel with four cell lines and seven healthy volunteers. Our findings revealed that ddPCR effectively classified normal CNV groups—including normal control cell lines, healthy volunteers, and samples with normal MLPA final ratios—from deletion groups, which included deletion control cell lines, samples with deletion final ratios from MLPA, and cases with previously ambiguous results. Interestingly, two cases involving BRCA1 and one case involving BRCA2 exhibited ambiguous results using MLPA; however, ddPCR enabled more precise classification by applying the Youden Index from ROC analysis and identifying optimal cutoff values of 1.35 for BRCA1 and 1.55 for BRCA2. These optimal thresholds allowed ddPCR to effectively reclassify the ambiguous MLPA cases into the deletion group. Overall, ddPCR could offer a more sensitive and reliable approach for CNV detection in heterogeneous tissue samples and demonstrates strong potential as a biomarker tool for guiding targeted therapy in advanced prostate cancer patients. However, further validation in larger cohorts is necessary to optimize cutoff precision, confirm diagnostic performance, and evaluate the full clinical utility of ddPCR. Full article

Gleason score (GS) is one of the best predictors of prostate cancer (PCa) aggressiveness; however, its biological features need to be elucidated. This study aimed to explore the biological characteristics of localized/locally advanced PCa stratified using in silico GS analysis. Biological features were analyzed using gene set variation analysis and the xCell algorithm with mRNA expression in two independent public databases: The Cancer Genome Atlas (TCGA) (n = 493; radical prostatectomy cohort) and GSE116918 (n = 248; radiation therapy cohort). GS levels were positively correlated with the activity levels of cell proliferation-related gene sets, including E2F targets, the G2M checkpoint, the mitotic spindle, and MYC targets v1 and v2 in both cohorts. Furthermore, GS levels were positively associated with the activity levels of immune-related gene sets and infiltrating fractions of immune cells, including CD4+ memory T cells, dendritic cells, M1 macrophages, and Th2 cells, in both cohorts. Notably, GS levels were positively associated with the score levels of homologous recombination defects, intratumor heterogeneity, fraction genome alteration, neoantigens, and mutation rates in the TCGA cohort. In conclusion, PCa with high GS levels was associated with cancer cell proliferation, immune cell infiltration, and high mutation rates, which may reflect worse clinical outcomes. Full article

Cancer remains a leading global health burden, profoundly affecting patient survival and quality of life. Current treatments—including chemotherapy, radiotherapy, immunotherapy, and surgery—are often limited by toxicity or insufficient specificity. Conventional chemotherapy, for instance, indiscriminately attacks rapidly dividing cells, causing severe side effects. In contrast, peptide-based therapeutics offer a paradigm shift, combining high tumour-targeting precision with minimal off-target effects. Their low immunogenicity, multi-pathway modulation capabilities, and adaptability for diagnostics and therapy make them ideal candidates for advancing oncology care. Innovative peptide platforms now enable three transformative applications: (1) precision molecular diagnostics (e.g., ¹⁸F-PSMA-1007 for prostate cancer detection), (2) targeted therapies (e.g., BT5528 and SAR408701 targeting tumour-specific antigens), and (3) theranostic systems (e.g., RAYZ-8009 and ¹⁷⁷Lu-FAP-2286 integrating imaging and radiotherapy). Despite their promise, peptides face challenges like metabolic instability and short half-lives. Recent advances in structural engineering (e.g., cyclization and D-amino acid incorporation) and delivery systems (e.g., nanoparticles and PEGylation) have significantly enhanced their clinical potential. This review highlights peptide-based agents in development, showcasing their ability to improve early cancer detection, reduce metastasis, and enhance therapeutic efficacy with fewer adverse effects. Examples like CLP002 underscore their role in personalised medicine. By overcoming current limitations, peptide drugs are poised to redefine cancer management, offering safer, more effective alternatives to conventional therapies. Their integration into clinical practice could mark a critical milestone in achieving precision oncology. Full article

Objective: Radical therapies are associated with significant morbidity in patients with localized prostate cancer (PCa). While advances in nuclear magnetic resonance techniques have enabled the development of focal ablation procedures that can selectively destroy tumors, preserve the gland and surrounding structures, and minimize side effects, existing vascular-targeted photodynamic therapy (VTP) and nanodrug therapies often face limitations, such as recurrence and insufficient drug concentration at the tumor site. This study investigated a novel approach that combines VTP with systemic treatment using drug-loaded nanoparticles in a murine model, demonstrating substantial advancements beyond current monotherapies. Methods: SCID (severe combined immunodeficiency) mice were engrafted with androgen-sensitive prostate tumor cells (LNCaP-AR) and treated with a combination of VTP and two different drugs linked to fucoidan nanoparticles (Enzalutamide and Paclitaxel). Experiments were performed using different cohorts: the evaluation of oncological effect, the administration time and concentration of systemic therapy, a comparison of efficacy between VTP and radiotherapy, and the induction of the abscopal effect in untreated synchronous tumors. Results: The groups that received combination therapy showed better tumor control. After eight weeks, the recurrence-free survival rates were 87.5%, 62.5%, and 50% in the VTP + N-PAC, VTP + N-ENZ, and VTP monotherapy groups, respectively (p < 0.05). There was a significant difference in the intra-tumoral concentration of nanodrugs between the groups with combined treatment and monotherapy. After two weeks, the monotherapy groups showed almost total elimination of the drugs, whereas in the combined therapy groups, this concentration remained high, starting to decrease after three weeks (p < 0.05). Treatment with nanodrugs associated with VTP showed superior oncological benefits compared to radiotherapy alone or in combination with other therapies. The abscopal effect on synchronous tumors was not demonstrated with VTP alone or in combination with nanodrugs. Conclusions: Combining vascular photodynamic therapy with nanodrugs was highly effective in treating a prostate tumor model, leading to increased survival and a reduced risk of tumor recurrence. This approach significantly advances beyond existing VTP and nanodrug therapies by improving tumor control, ensuring sustained intra-tumoral drug concentration, and yielding superior oncological outcomes. Our results suggest that this therapy is a potential treatment option for prostate tumors treated with VTP in future clinical trials. Full article

Prostate cancer, a malignancy of significant prevalence, affects approximately half a million men in Europe, with one in twelve males receiving a diagnosis before reaching the age of 75. Radiotheranostics represents a paradigm shift in prostate cancer treatment, leveraging radionuclides for diagnostic and therapeutic applications, with PSMA emerging as the primary molecular target. Regulatory bodies have approved various PSMA-targeted radiodiagnostic agents, such as [¹⁸F]DCFPyL (PYLARIFY^®, Lantheus Holdings), [¹⁸F]rhPSMA-7.3 (POSLUMA^®, Blue Earth Diagnostics), and [⁶⁸Ga]Ga-PSMA-11 (LOCAMETZ^®, Novartis/ILLUCCIX^®, Telix Pharmaceuticals), as well as therapeutic agents like [¹⁷⁷Lu]Lu-PSMA-617 (PLUVICTO^®, 15 Novartis). The approval of PLUVICTO^® in March 2022 for patients with metastatic castration-resistant prostate cancer who have undergone prior treatments, including androgen receptor pathway-targeting agents and taxane-based chemotherapy, represents a significant advancement. Other radionuclides like ¹⁶¹Tb, ¹⁴⁹Tb, ²²⁵Ac, ²²⁷Th, ²²³Ra, ²¹¹At, ²¹³ Bi, ²¹²Pb, ⁸⁹Zr, and ¹²⁵I are presented, emphasizing their clinical implementation or the stage of clinical trial they are in in the flow to biomedical implementation. Three clinically wise used radionuclides ¹⁷⁷Lu, ²²⁵Ac, ²²³Ra are shown along with their characteristics. This review aims to elucidate the molecular mechanisms underpinning PSMA, explore the clinical applications of PSMA-targeted radiotheranostics, and critically examine the diverse challenges these therapies encounter in the treatment of prostate cancer. Full article

Jumping translocations (JTs) are rare chromosomal abnormalities that play a crucial role in the pathogenesis of various cancer types. These rearrangements, especially those involving chromosome 1q, are frequently associated with tumor progression, therapeutic resistance, and poor prognosis. One gene of particular interest, human Jumping Translocation Breakpoint (JTB), has been identified at the site of translocation breakpoints and exhibits complex, context-dependent roles in cancer biology. JTB protein functions as a pivotal regulator in mitosis, chromosomal segregation, apoptosis, and cellular metabolism. It is functionally linked with the chromosomal passenger complex (CPC) and is implicated in processes such as epithelial–mesenchymal transition (EMT), immune evasion, and therapy resistance, especially in breast and prostate cancers. Advances in genomic, transcriptomic, and proteomic research have highlighted the significant potential of JTB as a diagnostic biomarker and a target for therapeutic interventions. This review underscores the dual role of JTB as both a tumor suppressor and oncogene, depending on the cellular context, and advocates for its continued investigation at the genomic, transcriptomic, and proteomic levels. Understanding JTB’s multifaceted contributions to tumor biology may pave the way for novel biomarkers and targeted treatments in cancer management. Full article