Search Results (59)

The treatment of choice for prostate cancer is androgen deprivation (ADT) and novel hormonal agents such as Abiraterone, Enzalutamide, or Apalutamide. Initially, this therapy is highly effective, but a significant challenge arises as most patients eventually develop resistance, resulting in castration-resistant prostate cancer (CRPC). Furthermore, the sequential use of these drugs can lead to cross-resistance, diminishing their efficacy. Tumor heterogeneity plays a pivotal role in the development of resistance to different treatments. This study utilized cellular models of CRPC to assess the response to Apalutamide when it was administered as a second- or third-line treatment. Functional and genetic analyses were conducted in various CRPC cell models exposed to Apalutamide. These analyses included real-time cell monitoring assays, flow cytometry, clonogenicity assays, and RT-qPCR. CRPC cell models were capable of continued proliferation, maintained cell cycle profiles similar to those of untreated cells, and retained their clonogenic potential. Cross-resistance to Apalutamide in models of ADT, ADT plus Enzalutamide, or Abiraterone resistance did not correlate with the expression levels of AR-V7 and AR-V9 variants. Gene expression analysis of resistant prostate cancer cell lines revealed that treatment with Apalutamide induced the emergence of more aggressive phenotypes, including cancer stem cells or neuroendocrine differentiation profiles. Most CRPC cell models developed cross-resistance to Apalutamide and were able to proliferate and retain their clonogenic capability. Apalutamide resistance was not linked to the expression of AR-V7 or AR-V9 variants but was instead associated to bypass of AR signaling pathway and the emergence of more aggressive expression profiles. Full article

Background/Objectives: Prostate cancer is the most common cancer among men globally and a leading cause of cancer-related death. Germline genetic evaluation is increasingly recognized as essential for men with high-risk features such as a strong family history or advanced disease. Methods: Comprehensive genetic risk assessment should integrate three components: family history (FH), rare pathogenic mutations (RPMs), and polygenic risk scores (PRS). RPMs in DNA repair genes (e.g., BRCA2, CHEK2, ATM) can inform screening, prognosis, and treatment strategies, particularly for metastatic or aggressive disease. PRS, derived from common genetic variants, provides a personalized and independent measure of prostate cancer risk and may guide decisions on screening intensity and timing. Results: Although PRS cannot yet differentiate between indolent and aggressive cancer, it has the potential to stratify men into low and high-risk categories more effectively than FH or RPMs alone. Knowledge of specific RPMs can influence treatment decisions in clinically advanced prostate cancer. Challenges in clinical implementation include limited provider awareness, underutilization of genetic counseling, and lack of diversity in genomic datasets, which can lead to misdiagnoses. Emerging technologies and digital tools are being developed to streamline genetic testing and counseling. Population-level strategies and tailored screening protocols based on genetic risk are under active investigation. Conclusions: While early evidence suggests high satisfaction with genetic testing among patients, further studies in diverse populations are needed. Integration of germline genetic information into prostate cancer management offers promising avenues for personalized screening, surveillance, and treatment, ultimately aiming to reduce morbidity and mortality. Full article

Alterations in aggressive-variant prostate cancer-associated tumor suppressor genes (AVPC-TSG: TP53, RB1, PTEN) are related with androgen insensitivity and aggressive disease. However, their prognostic and predictive role in metastatic hormone-sensitive prostate cancer (mHSPC) is unclear. This single-center retrospective study assesses the value of AVPC-TSG alterations in refining prognosis and predicting the response to androgen receptor pathway inhibitors (ARPIs) in mHSPC. We included 158 patients with genomic tumor sequencing undergoing treatment for mHSPC between 2013 and 2023. We compared patients with AVPC-TSGalt tumors (≥1 alteration in TP53, RB1, or PTEN/PI3K/AKT pathway genes) to those with AVPC-TSGwt tumors (i.e., without alterations in AVPC-TSG). Cox analyses were performed for progression-free survival (PFS) and overall survival (OS). AVPC-TSGwt status was associated with improved PFS and OS in both univariate and multivariate (MV) analyses (MV PFS: HR 0.58, 95%CI: 0.38–0.89, p = 0.012; MV OS: HR 0.48, 95%CI: 0.26–0.91, p = 0.025). AVPC-TSGalt mHSPC patients seemed to derive no PFS benefit from ARPI addition (PFS: HR 1.13, 95%CI: 0.58–2.19, p = 0.721), while AVPC-TSGwt mHSPC patients did (PFS: HR 0.51, 95%CI: 0.28–0.93 p = 0.029). Integrating AVPC-TSG status with CHAARTED volume criteria, we identified three distinct subgroups: “good risk” (AVPC-TSGwt low volume), “intermediate risk” (either AVPC-TSGalt low volume or AVPC-TSGwt high volume), and “poor risk” (AVPC-TSGalt high volume) with median PFS of 46.8, 28.2, and 15.7 months, respectively. Only the “intermediate risk” subgroup seemed to derive PFS benefit from ARPI addition (HR 0.36, 95%CI: 0.19–0.70, p = 0.002). AVPC-TSG status assessment refines prognosis and may predict PFS benefits of ARPIs in mHSPC. AVPC-TSGalt mHSPC patients should be considered for clinical trials as they may not benefit from current standard approaches. Full article

Background: Advancing chimeric antigen receptor (CAR) T cell therapy for solid tumors remains a major challenge in cancer immunotherapy. Prostate cancer (PCa), particularly in its aggressive forms, may be a suitable target for CAR-T therapy given the range of associated tumor antigens. However, due to the high plasticity and heterogeneity of aggressive PCa and the complexity of the tumor environment, there is a need to broaden the repertoire of targetable antigens and deepen our understanding of CAR-T behavior in stressed microenvironmental conditions. Growing evidence supports mesothelin as a promising cancer-associated marker and a compelling target for CAR-T cell approaches in solid tumors. Objectives and Methods: Here, we employed gene expression datasets to investigate mesothelin expression in both primary and metastatic PCa tumors. Additionally, we evaluated mesothelin expression across various preclinical PCa models and assessed the therapeutic efficacy of second-generation mesothelin-targeted CAR-T (meso-CAR-T) cells under both normoxic and hypoxic conditions, with hypoxia as a representative tumor-associated stress condition. Results: Our results revealed a significant enrichment of mesothelin in 3–10% of metastatic prostate tumors, contrasting with its minimal expression in primary tumors. In line with these findings, we observed increased mesothelin expression in an aggressive variant of the 22Rv1 cell line, which displayed an epithelial–mesenchymal plasticity (EMP) phenotype. Meso-CAR-T cells demonstrated potent cytotoxicity and remarkable selectivity toward these carcinoma cells under both severe hypoxia (1% O₂) or normoxia (21% O₂), highlighting their ability to withstand metabolic stress within the tumor microenvironment. Conclusions: Our study underscores the potential of meso-CAR-T cells as a promising strategy for targeting specific subtypes of metastatic prostate cancer. Full article

This review is intended to reflect the currently available literature on both clinically significant germline mutations in DNA damage repair (DDR) genes as well as the importance of ancestral diversity in the pathogenesis of prostate cancer (PCa). The second most prevalent cancer worldwide in men is PCa, causing significant morbidity and mortality in its advanced stage. Emerging data highlight the substantial role of germline mutations of DDR genes in PCa pathogenesis, especially in progression to aggressive forms of the disease. Germline genetic testing is recognized as a necessary tool for efficient, individualized patient care. NCCR guidelines recommend inquiring about the family history of PCa and known germline variants and, if indicated, proceeding with germline multigene testing followed by post-test genetic counseling. Depending on the germline mutations in HR repair genes or in MMR genes, specific treatment options may provide clinical benefit. We will discuss specific germline mutations that are involved in PCa progression and prognosis in racially diverse populations. Full article

Background: Prostate cancer (PC) is one of the most common oncological diseases among men. Up to 20% of PC cases are associated with hereditary risks or syndromes. The impact of common variants, particularly EHBP1 c.1185+30064G>A rs721048, on developing PC and other malignancies remains unclear. There are also no data on the frequency of this variant in the Kazakh population or its association with PC, nor its potential connection with other malignancies, particularly colorectal cancer (CRC). Methods: We utilized the TruSight Cancer Sequencing Panel to assess pathological genomic variants in 72 male patients with histologically verified aggressive PC and 119 patients of Kazakh nationality with histologically confirmed CRC compared to the control group. Results: A variant in the intron of the EHBP1 gene c.1185+30064G>A rs721048 was identified in 18 patients (25%) out of 72 with PC, while in the control group of 41 healthy males, the rs721048 variant was found in only 4 (9.8%) individuals. In the CRC group, rs721048 was detected in 17 cases (14.2%) and eight control individuals (10%). Conclusions: The frequency of the EHBP1 c.1185+30064G>A rs721048 variant in the PC group was significantly higher (p < 0.05) than in healthy males of Kazakh nationality. Identifying EHBP1 c.1185+30064G>A among the male population of Kazakhstan will help form the high-risk groups for PC to prevent the development of malignant neoplasms. The presence of rs721048 was not significantly associated with the risk of developing CRC in our study. Full article

It has been shown that the pathogenic variants (PVs) of the DNA Damage Response (DDR) genes, whether of a germinal or somatic nature, represent a predictive biomarker of high sensitivity to treatment with inhibitors of the enzyme poly-ADP-ribose polymerase (PARP) in patients with hormone-resistant metastatic prostate cancer (HRPCa). Moreover, the detection of PVs of the Homologous Recombination Repair (HRR) genes in PCa patients can help to define the patient’s prognosis and the choice of the therapeutic procedure. Among men with metastatic PCa, the frequency of PVs in HRR genes ranges from 11% to 33%, which is a significantly higher rate compared to non-metastatic PCa, where the incidence is between 5% and 10%. Next-Generation Sequencing (NGS) results were more commonly obtained from newly acquired somatic samples compared to archived samples (prostate biopsy or prostatectomy). We developed an experimental multidisciplinary prospective study in patients with a new diagnosis of high-risk PCa at biopsy. The aim was to evaluate the presence of PVs of different HRR genes in patients with the first diagnosis of PCa in relation to a metastatic or non-metastatic stage, tumor aggressiveness, and early risk of progression. Among 43 initial tumor samples from 22 patients, 25 samples from 12 patients were selected for library preparation based on their DNA concentration and quality. After the NGS, 14 different DNA variants were prioritized. Oncogenetic and likely oncogenetic variants were found in the ATM, BRCA1, PTEN, KMT2D, and CDH1 genes. Moreover, variants of uncertain significance were found in ATM, DDR2, FANCA, FOXA1, PLCB4, PTCH1, and RB1. Full article

Androgen-indifferent prostate cancer (AIPC) is increasingly common and particularly lethal. Data describing these tumors are sparse, and AIPC remains a poorly understood malignancy. Utilizing the Oncology Research Information Exchange Network (ORIEN) database, we enriched for tumors with features of AIPC using previously described characteristics. Our AIPC cohort included three subgroups: aggressive variant prostate cancer (AVPC), neuroendocrine PC (NEPC), and double-negative PC (DNPC). Of 1496 total PC patients available for analysis, we identified 323 (22%) as MCRPC. Of those, 39 (12%) met AIPC criteria (17 AVPC, 13 NEPC, 9 DNPC) and 284 (88%) were non-AIPC. Forty-three percent of AIPC patients had de novo metastatic disease vs. 15% for non-AIPC (p = 0.003). Homologous recombination deficiency (HRD) and tumor mutational burden (TMB) did not differ between cohorts, but microsatellite instability scores (MSI) were significantly higher in AIPC (p = 0.019). Using Gene Set Enrichment Analysis (GSEA), we found that genes defining response to androgens and genes involved in oxidative phosphorylation were the most downregulated, whereas genes involved in epithelial–mesenchymal transition (EMT) and immune signaling were significantly upregulated in AIPC vs. non-AIPC. Our study demonstrates the potential for predefined criteria that aim to enrich for AIPC and suggests opportunities for therapeutic investigation. Full article

Aggressive variant prostate cancer (AVPC) is characterized by a molecular signature involving combined defects in TP53, RB1, and/or PTEN (AVPC-TSGs), identifiable through immunohistochemistry or genomic analysis. The reported prevalence of AVPC-TSG alterations varies widely, reflecting differences in assay sensitivity, treatment pressure, and disease stage evolution. Although robust clinical evidence is still emerging, the study of AVPC-TSG alterations in prostate cancer (PCa) is promising. Alterations in TP53, RB1, and PTEN, as well as the combined loss of AVPC-TSGs, may have significant implications for prognosis and treatment. These biomarkers might help predict responses to various therapies, including hormonal treatments, cytotoxic agents, radiotherapy, and targeted therapies. Understanding the impact of these molecular alterations in patients with PCa is crucial for personalized management. In this review, we provide a comprehensive overview of the emerging prognostic and predictive roles of AVPC-TSG alterations across PCa stages. Moreover, we discuss the implications of different methods used for detecting AVPC-TSG alterations and summarize factors influencing their prevalence. As our comprehension of the genomic landscape of PCa disease deepens, incorporating genomic profiling into clinical decision making will become increasingly important for improving patient outcomes. Full article

Background/Objectives: Androgen receptor (AR) expression and signaling are critical for the progression of prostate cancer and have been the therapeutic focus of prostate cancer for over 50 years. While a variety of agents have been developed to target this axis, many of these fail due to the emergent expression of AR RNA splice variants, such as AR-V7, that can signal independently of ligand binding. Other therapies, such as vaccination against prostate-specific antigens, have achieved FDA approvals but have fallen short of being incorporated as standard-of-care therapies for advanced prostate cancer. This may be due to the elevated level of immunosuppression observed in prostate cancer, which remains largely refractory to immune checkpoint blockade. Methods: We developed a vaccine targeting AR-V7, a common isoform associated with treatment resistance, and demonstrated its ability to elicit AR-V7-specific immunity and enable anti-tumor responses against AR-V7+ cancers in subcutaneous tumor models. Results: Our studies also revealed that AR-V7 expression conferred an immune suppressive phenotype that was significant in a non-AR-dependent prostate cancer model. Notably, in this model, we found that vaccination in combination with enzalutamide, an AR antagonist, suppressed these aggressive immune suppressive cancers and resulted in enhanced survival in comparison to control vaccinated and enzalutamide-treated mice. While anti-PD-1 immune checkpoint inhibition (ICI) alone slowed tumor growth, the majority of vaccinated mice that received anti-PD-1 therapy showed complete tumor elimination. Conclusions: Collectively, these results validate the importance of AR signaling in prostate cancer immune suppression and suggest the potential of AR-V7-specific vaccines as therapeutic strategies against prostate cancer, offering significant protective and therapeutic anti-tumor responses, even in the presence of androgen signaling inhibitors. Full article

Cytochrome c (Cytc) is important for both mitochondrial respiration and apoptosis, both of which are altered in cancer cells that switch to Warburg metabolism and manage to evade apoptosis. We earlier reported that lysine 53 (K53) of Cytc is acetylated in prostate cancer. K53 is conserved in mammals that is known to be essential for binding to cytochrome c oxidase and apoptosis protease activating factor-1 (Apaf-1). Here we report the effects of this acetylation on the main functions of cytochrome c by expressing acetylmimetic K53Q in cytochrome c double knockout cells. Other cytochrome c variants analyzed were wild-type, K53R as a control that maintains the positive charge, and K53I, which is present in some non-mammalian species. Intact cells expressing K53Q cytochrome c showed 49% decreased mitochondrial respiration and a concomitant increase in glycolytic activity (Warburg effect). Furthermore, mitochondrial membrane potential was decreased, correlating with notably reduced basal mitochondrial superoxide levels and decreased cell death upon challenge with H₂O₂ or staurosporine. To test for markers of cancer aggressiveness and invasiveness, cells were grown in 3D spheroid culture. K53Q cytochrome c-expressing cells showed profoundly increased protrusions compared to WT, suggesting increased invasiveness. We propose that K53 acetylation of cytochrome c is an adaptive response that mediates prostate cancer metabolic reprogramming and evasion of apoptosis, which are two hallmarks of cancer, to better promote tumor survival and metastasis. Full article

Background: Prostate cancer is a malignant neoplasm of the male genitourinary system with the highest incidence worldwide. Susceptibility genes related to aggressiveness and prognosis, such as BRCA1/2, ATM, PTEN, have been identified. Currently, reports related to germline mutations in patients with prostate cancer in Latin American populations are very limited or absent. In the Mexican population, reports are also limited, especially in the context of metastatic prostate cancer. Determining the prevalence of these mutations is relevant to predict the potential aggressiveness of tumors and allow the use of targeted therapies, such as PARPi inhibitors. Objective: Determine the prevalence of germline mutations in patients with metastatic prostate cancer and establish their clinical characteristics at diagnosis. Material and Methods: Sixty-nine patients with metastatic PCa underwent testing and genetic analysis using the Comprehensive Multi-Cancer Hereditary Cancer Panel. The prevalence of germline mutations was assessed, and the cohort was divided into two groups for the evaluation and analysis of clinical characteristics between the mutated and non-mutated populations. Results: We identified mutations in 15 out of 69 patients (21.73%), while 54 patients (78.26%) had no mutations. Pathogenic mutations were observed in 15.9% of patients, Variants of Uncertain Significance (VUS) in 34.78%, and 5.79% had both. The most frequent mutations included ATM (11.54%), BRCA1 (11.54%), BRCA2 (7.69%), FANCA (7.69%), and FANCM (7.69%). No statistically significant differences were found in PSA levels, age at diagnosis, and resistance to castration between the two groups. Conclusions: Our study unveiled a mutation rate of 21.73%, marked by a significant prevalence of ATM, FANCA, FANCM, and Variants of Uncertain Significance (VUS). This pattern deviates from findings in other series, underscoring the necessity for improved access to clinical genetic testing in our population. Full article

Prostate cancer accounts for 29% of malignant diagnoses among men in the United States and is the second leading cause of death from cancer. Effective screening methods and improved treatment have decreased the mortality rate significantly. This decreased mortality rate, however, does not apply to all histologic variants. Adenosquamous carcinoma of the prostate is an extremely aggressive neoplasm with no current known curative therapy. It is often diagnosed after chemotherapy, radiation, or androgen deprivation therapy for traditional prostatic adenocarcinomas. Primary carcinomas of the prostate with squamous features include, but are not limited to, pure squamous cell carcinoma and adenocarcinoma mixed with squamous cell carcinoma (SCC). Important distinguishable clinical features of adenosquamous carcinoma include normal prostate-specific antigen (PSA) levels, even with advanced disease and osteolytic versus osteoblastic metastatic lesions in adenocarcinoma. Additional entities to consider in the differential diagnosis are squamous metaplasia of the prostate, secondary involvement of pure SCC, and urothelial carcinoma with squamous differentiation. Here, we present a de novo case of adenosquamous carcinoma in a 48-year-old man who rapidly developed extensive metastatic disease. Full article

Ductal adenocarcinoma of the prostate (DAP) is an uncommon variant of prostate cancer associated with aggressive disease and poor outcome. It presents most frequently as a mixed tumor combined with acinar adenocarcinoma. Although the histopathological features of DAP are well known, its genomic characteristics are still evolving, prompting the suggestion that all DAP would benefit from molecular analysis with the purpose of improving tumor recognition, genetic classification, and, ultimately, personalized therapy. Herein, we report a case of DAP with novel genetic alterations (BCOR P1153S, ERG M219I, KDR A750E, POLE S1896P, and RAD21 T461del). Full article

Prostate cancer (PC) is a common malignancy among elderly men, characterized by great heterogeneity in its clinical course, ranging from an indolent to a highly aggressive disease. The aggressive variant of prostate cancer (AVPC) clinically shows an atypical pattern of disease progression, similar to that of small cell PC (SCPC), and also shares the chemo-responsiveness of SCPC. The term AVPC does not describe a specific histologic subtype of PC but rather the group of tumors that, irrespective of morphology, show an aggressive clinical course, dictated by androgen receptor (AR) indifference. AR indifference represents an adaptive response to androgen deprivation therapy (ADT), driven by epithelial plasticity, an inherent ability of tumor cells to adapt to their environment by changing their phenotypic characteristics in a bi-directional way. The molecular profile of AVPC entails combined alterations in the tumor suppressor genes retinoblastoma protein 1 (RB1), tumor protein 53 (TP53), and phosphatase and tensin homolog (PTEN). The understanding of the biologic heterogeneity of castration-resistant PC (CRPC) and the need to identify the subset of patients that would potentially benefit from specific therapies necessitate the development of prognostic and predictive biomarkers. This review aims to discuss the possible pathophysiologic mechanisms of AVPC development and the potential use of emerging tissue-based biomarkers in clinical practice. Full article