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Our understanding of neuroendocrine prostate cancer (NEPC) has assumed a new perspective in light of the recent advances in research. Although classical NEPC is rarely seen in the clinic, focal neuroendocrine trans-differentiation of prostate adenocarcinoma occurs in about 30% of advanced prostate cancer (PCa) cases, and represents a therapeutic ch...
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Simple Summary
Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a subtype of castration-resistant prostate cancer (CRPC) which develops under prolonged androgen deprivation therapy. The mechanisms and pathways underlying the t-NEPC are still poorly understood and there are no effective treatments available. Here, we summarize the litera...
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... Trans-differentiation of prostate adenocarcinoma to acquire a neuroendocrine phenotype has been extensively investigated as a crucial mechanism for the development of NEPC, a highly aggressive and therapy-resistant phenotype of prostate cancer [19,22,30]. Emerging studies suggest that genes commonly upregulated in patients with a neuroendocrine phenotype regulate important neuronal functions and are associated with poor prognosis during cancer progression [22,28,29]. ...
Treatment-induced neuroendocrine prostate cancer (t-NEPC) often arises from adenocarcinoma via lineage plasticity in response to androgen receptor signaling inhibitors, such as enzalutamide. However, the specific regulators and targets involved in the transition to NEPC are not well understood. Plexin D1 (PLXND1) is a cellular receptor of the semaphorin (SEMA) family that plays important roles in modulating the cytoskeleton and cell adhesion. Here, we found that PLXND1 was highly expressed and positively correlated with neuroendocrine markers in patients with NEPC. High PLXND1 expression was associated with poorer prognosis in prostate cancer patients. Additionally, PLXND1 was upregulated and negatively regulated by androgen receptor signaling in enzalutamide-resistant cells. Knockdown or knockout of PLXND1 inhibited neural lineage pathways, thereby suppressing NEPC cell proliferation, patient derived xenograft (PDX) tumor organoid viability, and xenograft tumor growth. Mechanistically, the heat shock protein 70 (HSP70) regulated PLXND1 protein stability through degradation, and inhibition of HSP70 decreased PLXND1 expression and NEPC organoid growth. In summary, our findings indicate that PLXND1 could serve as a promising therapeutic target and molecular marker for NEPC.
... Of high clinical importance is the exploration of neuroendocrine transdifferentiation, which is an AR-independent resistance mechanism in CRPC. While the incidence of neuroendocrine PC is rising, its early detection and treatment remain difficult and improvements are urgently needed (8,47,48). Thanks to the CoDuCo in situ assay's improved multiplexing capability, we were able to add markers relevant for neuroendocrine PC to our panel. We visualized SYP, CHGA, and NCAM1 transcripts as pooled neuroendocrine markers to identify CTCs with neuroendocrine features, as well as DLL3 and SLFN11 as potential predictive markers. ...
Metastatic prostate cancer is a highly heterogeneous and dynamic disease and practicable tools for patient stratification and resistance monitoring are urgently needed. Liquid biopsy analysis of circulating tumor DNA and circulating tumor cells (CTCs) are promising, but due to the diversity of resistance mechanisms, comprehensive testing is essential. Previously, we demonstrated that CTCs can be characterized by mRNA-based in situ padlock probe hybridization. Now, we have developed a novel combinatorial dual-color (CoDuCo) approach with increased multiplex capacity of up to 15 distinct markers, complemented by semi-automated image analysis and machine learning-assisted CTC classification. Here, we present three exemplary cases of patient samples in which the CoDuCo assay visualized diverse resistance mechanisms (AR-V7, neuroendocrine differentiation (SYP, CHGA, NCAM1)), as well as druggable targets and predictive markers (PSMA, DLL3, SLFN11). The combination of high multiplex capacity and microscopy-based single-cell analysis is a unique and powerful feature of the CoDuCo in situ assay. This synergy enables the identification and characterization of CTCs with epithelial, epithelial-mesenchymal, and neuroendocrine phenotypes, the detection of CTC clusters, and the visualization of CTC heterogeneity. In conclusion, the assay is a promising tool for monitoring the dynamic molecular changes associated with drug response and resistance in prostate cancer.
... We should point out that a small number of NE cells are found in the normal prostate gland. However, ADT drives the appearance of foci of NE cells, leading to the formation of therapy-induced neuroendocrine prostate cancer (t-NEPC) [13,14]. It has Figure 1. ...
... We should point out that a small number of NE cells are found in the normal prostate gland. However, ADT drives the appearance of foci of NE cells, leading to the formation of therapy-induced neuroendocrine prostate cancer (t-NEPC) [13,14]. It has been reported that approximately 20-25% of patients with CRPC show evidence of t-NEPC [15,16]. ...
Androgen receptor signaling regulates the normal and pathological growth of the prostate. In particular, the growth and survival of prostate cancer cells is initially dependent on androgen receptor signaling. Exposure to androgen deprivation therapy leads to the development of castration-resistant prostate cancer. There is a multitude of molecular and cellular changes that occur in prostate tumor cells, including the expression of neuroendocrine features and various biomarkers, which promotes the switch of cancer cells to androgen-independent growth. These biomarkers include transcription factors (TP53, REST, BRN2, INSM1, c-Myc), signaling molecules (PTEN, Aurora kinases, retinoblastoma tumor suppressor, calcium-binding proteins), and receptors (glucocorticoid, androgen receptor-variant 7), among others. It is believed that genetic modifications, therapeutic treatments, and changes in the tumor microenvironment are contributing factors to the progression of prostate cancers with significant heterogeneity in their phenotypic characteristics. However, it is not well understood how these phenotypic characteristics and molecular modifications arise under specific treatment conditions. In this work, we summarize some of the most important molecular changes associated with the progression of prostate cancers and we describe some of the factors involved in these cellular processes.
... Важным механизмом возникновения резистентности РПЖ к гормональной терапии, как с применением агонистов ГнРГ, так и новых антиандрогенов, является НЭД опухолевых клеток, которую наблюдают у 25% пациентов с метастатическим РПЖ [13]. В экспериментах in vitro и in vivo было показано, что в условиях кастрационного уровня тестостерона клетки предстательной железы (ПЖ) приобретают фенотипические признаки нейронов, форма их становится более вытянутой, в цитоплазме появляются секреторные гранулы, что сопровождается увеличением экспрессии нейроэндокринных маркеров, снижением экспрессии АР и уровня ПСА [14,15]. ...
Introduction. Chromogranin A has the greatest diagnostic value in detecting neuroendocrine differentiation (NED) of a tumor. This work is devoted to the study of the therapy of castration-resistant prostate cancer (CRPC) using somatostatin (AS) analogues based on the assessment of the neuroendocrine status of the tumor. Material and methods. The study included 89 patients with CRPC aged 72.2±1.4 years. Localized prostate cancer was diagnosed in 6 (6.7%), locally distributed prostate cancer (T3-4N0M0) in 12 (13.5%) patients, metastatic (T3-4N0-1M1)–in 71 (79.8%). An increase in CgA was observed in 31.5% (n=28) of CRPC patients. Combination therapy was performed with Octreotide depot (Pharm–Sintez, Russia) according to the scheme: 20 mg n/a once every 28 days in combination with dexamethasone at a dose of 4 mg per day for 1 month. Then the dose of dexamethasone was reduced. Patients were monitored every 28 days. The effectiveness was evaluated by the dynamics of PSA and CgA, as well as (ultrasound, abdominal MSCT, pelvic MRI and osteoscintigraphy). According to PSA, the answer was considered to be a decrease in the median PSA, or a lack of growth of more than 10%. Results. In patients with normal levels of CgA after 3 months of treatment, the median PSA significantly increased: from 57.0 [29.8; 94] ng/ml initially to 89.0 [47.4; 131.9] ng/ml, which was 56.1%, the decrease in CgA was 9.5% (from 2.1 to 1.9 nmol/l). In patients with elevated levels of CgA, there was a decrease in the median PSA value by 35.7%, from 169.5 [66.3; 235.3] ng/ml to 109.0 [44.8; 236.9] and CgA by 25% – from 5.2 [3.6; 7.1] to 3.9 [2.3; 5.2]. The median values and the proportion of PSA reduction in the group of «responders» stratified by CgA levels before and after 3 months of treatment were, respectively: in the group with normal CgA values – 43.0 [16.5; 154.3] nmol/l and 15.2 [7.2; 48.8] nmol/l or 64.7%; with CgA 3-7 nmol/l – 160.5 [35.1; 278.6] nmol/l and 42.4 [14.1; 88.4] nmol/l or 73.6%; in patients with CgA more than 7 nmol/L – 166.5 [28.0; 222.0] nmol/l and 81.7 [16.4; 151.0] nmol/l or 50.9%. Conclusion. Early detection of NED in CRPC with the use of the CgA marker makes it possible to stratify patients according to its severity and off r combination therapy with the inclusion of AS. An analysis of the immediate results of treatment with octreotide depot in combination with GnRH agonists and dexamethasone showed significantly higher efficacy in patients with initially increased levels of CgA, and the results achieved look preferable in patients with a moderate increase in this marker (within 3-7 nmol/l).
... Trans-differentiation of prostate adenocarcinoma to acquire a neuroendocrine phenotype has been extensively investigated as a crucial mechanism for the development of NEPC, a highly aggressive and therapy-resistant phenotype of prostate cancer [22,25,33]. Emerging studies suggest that genes commonly upregulated in patients with a neuroendocrine phenotype regulate important neuronal functions and are associated with poor prognosis during cancer progression [22,31,32]. ...
Treatment-induced neuroendocrine prostate cancer (t-NEPC) often arises from adenocarcinoma via lineage plasticity in response to androgen receptor signaling inhibitors, such as enzalutamide. However, the specific regulators and targets involved in the transition to NEPC are not well understood. Plexin D1 (PLXND1) is a cellular receptor of the semaphorin (SEMA) family that plays important roles in modulating the cytoskeleton and cell adhesion. Here, we found that PLXND1 is highly expressed and positively correlated with neuroendocrine markers in patients with NEPC. High PLXND1 expression is associated with poorer prognosis in prostate cancer patients. Additionally, PLXND1 was upregulated and negatively regulated by androgen receptor signaling in enzalutamide-resistant cells. Knockdown or knockout of PLXND1 inhibit neural lineage pathways, suppressing NEPC cell proliferation, PDX tumor organoid viability, and xenograft tumor growth. Mechanistically, the chaperone protein HSP70 regulates PLXND1 protein stability through degradation, and inhibition of HSP70 decreases PLXND1 expression and NEPC organoid growth. In summary, our findings suggest that PLXND1 could be a new therapeutic target and molecular indicator for NEPC.
... However, a larger proportion of treatment-induced neuroendocrine prostate cancer (t-NEPC) has been reported. Recent studies have indicated that approximately 17-30% of CRPC patients, following ADT and other treatments, may experience progression to t-NEPC [47,48]. The majority of evidence suggests that the origin of tNEPC is the transdifferentiation of adenocarcinoma cells into NEPC cells in response to different therapies, including ADT [47][48][49]. ...
... However, a larger proportion of treatmentinduced neuroendocrine prostate cancer (t-NEPC) has been reported. Recent studies have indicated that approximately 17-30% of CRPC patients, following ADT and other treatments, may experience progression to t-NEPC [47,48]. The majority of evidence suggests that the origin of tNEPC is the transdifferentiation of adenocarcinoma cells into NEPC cells in response to different therapies, including ADT [47][48][49]. ...
... Recent studies have indicated that approximately 17-30% of CRPC patients, following ADT and other treatments, may experience progression to t-NEPC [47,48]. The majority of evidence suggests that the origin of tNEPC is the transdifferentiation of adenocarcinoma cells into NEPC cells in response to different therapies, including ADT [47][48][49]. The transition to the NEPC phenotype following ADT treatments has been demonstrated in various preclinical models, including cell lines, genetically engineered mouse (GEM), and patient-derived xenografts [50][51][52]. ...
Simple Summary
Castration-resistant prostate cancer (CRPC) remains a significant medical challenge, even with recent advancements in diagnosis and treatment. To improve patient outcomes, it is important to understand the underlying mechanisms of resistance to treatments and develop new therapeutic approaches. This review provides a brief summary of the current knowledge on the mechanisms that contribute to CRPC progression, including both androgen receptor (AR)-dependent and AR-independent pathways. It also discusses approved and currently investigated treatment options to treat patients with CRPC, such as novel chemotherapies, radiation therapy, immunotherapy, PARP inhibitors, and potential combined therapeutic strategies.
Abstract
Prostate cancer (PC) is the second most common cancer in men worldwide. Despite recent advances in diagnosis and treatment, castration-resistant prostate cancer (CRPC) remains a significant medical challenge. Prostate cancer cells can develop mechanisms to resist androgen deprivation therapy, such as AR overexpression, AR mutations, alterations in AR coregulators, increased steroidogenic signaling pathways, outlaw pathways, and bypass pathways. Various treatment options for CRPC exist, including androgen deprivation therapy, chemotherapy, immunotherapy, localized or systemic therapeutic radiation, and PARP inhibitors. However, more research is needed to combat CRPC effectively. Further investigation into the underlying mechanisms of the disease and the development of new therapeutic strategies will be crucial in improving patient outcomes. The present work summarizes the current knowledge regarding the underlying mechanisms that promote CRPC, including both AR-dependent and independent pathways. Additionally, we provide an overview of the currently approved therapeutic options for CRPC, with special emphasis on chemotherapy, radiation therapy, immunotherapy, PARP inhibitors, and potential combination strategies.
... Несмотря на общие клинические, гистологические и некоторые молекулярные особенности с другими НЭК, включая мелкоклеточный рак легкого, НЭРПЖ является клональным производным от аденокарциномы предстательной железы [12][13][14][15]. ...
... Схема изменений в клетках рака предстательной железы, ведущих к нейроэндокринной дифференцировке (адаптировано из [15] с разрешения авторов). CREB -белок, связывающий ответный элемент цАМФ; EZH2 -фермент гистон-лизин-N-метилтрансфераза; SRRM4 -серин/аргининовая повторяющаяся матрица 4; PKCλ/ι -протеинкиназы Cλ/ι; c-Kit -рецептор тирозинкиназы; TP53 -белок-супрессор опухоли p53; RB1белок ретинобластомы 1; MIF -ингибитор миграции макрофагов; ADRP -белок, связанный с дифференцировкой адипоцитов; HMGB1 -белок группы высокой подвижности B1; mTOR -активатор мишени рапамицина; SCF -фактор стволовых клеток; PKD -протеинкиназа D Diagram of changes in prostate cancer tumor cells leading to neuroendocrine differentiation (adapted from [15] with permission from the authors). ...
... Схема изменений в клетках рака предстательной железы, ведущих к нейроэндокринной дифференцировке (адаптировано из [15] с разрешения авторов). CREB -белок, связывающий ответный элемент цАМФ; EZH2 -фермент гистон-лизин-N-метилтрансфераза; SRRM4 -серин/аргининовая повторяющаяся матрица 4; PKCλ/ι -протеинкиназы Cλ/ι; c-Kit -рецептор тирозинкиназы; TP53 -белок-супрессор опухоли p53; RB1белок ретинобластомы 1; MIF -ингибитор миграции макрофагов; ADRP -белок, связанный с дифференцировкой адипоцитов; HMGB1 -белок группы высокой подвижности B1; mTOR -активатор мишени рапамицина; SCF -фактор стволовых клеток; PKD -протеинкиназа D Diagram of changes in prostate cancer tumor cells leading to neuroendocrine differentiation (adapted from [15] with permission from the authors). CREB -cAMP response element binding protein; EZH2 -enhancer of zeste homolog 2; SRRM4 -serine/arginine repetitive matrix 4; PKCλ/ι -protein kinase C λ/ι; c-Kittyrosine kinase receptor; TP53 -tumor supressor protein p53; RB1 -retinoblastoma protein 1; MIF -migration inhibitory factor; ADRP -the adipocyte differentiationrelated protein; HMGB1 -high mobility group protein B1; mTOR -mammalian target of rapamycin; SCF -stem-cell factor; PKD -protein kinase D Нейроэндокринный рак предстательной железыагрессивный вариант КРРПЖ с плохим прогнозом. ...
In Russia, prostate cancer is a common disease with fast increasing incidence. In the vast majority of prostate cancer patients receiving hormone therapy, on average 18–36 months after the start of treatment refractoriness to androgen ablation develops. In 15–20 % of patients, signs of neuroendocrine differentiation may develop.Neuroendocrine prostate cancer is an aggressive variant of castration-resistant prostate cancer with poor prognosis and low survival.Due to the rarity of these types of tumors, specific diagnostic and treatment algorithms have not been developed. As a rule, they are similar to the methods for other malignant forms of prostate cancer and neuroendocrine tumors.
... CRPC is characterized by high heterogeneity in tissue morphology, cellular and molecular characteristics. Emerging single-cell and bulk transcriptomic studies of post-ADT tumors reveal high heterogeneity with a complex combination of cell types for majority retaining properties of prostate adenocarcinoma with still active AR signaling, but some progressively acquiring androgen independence (AI) and/or undergoing neuroendocrine (NE) trans-differentiation giving rise to tNEPC (Patel et al, 2019) ; (Beltran et al, 2019) ; (Beltran et al, 2012) ; (Labrecque et al, 2019) ; (Risbridger et al, 2021). However, these trajectories are not linear and prevailing, reflecting high lineage plasticity of advanced prostate cancer tumors due to multiple genetic alterations and activation of numerous reprogramming transcription factors (ONECUT2, BRN2, SOX2, OCT4, ASCL1) and chromatin modifies (EZH2, SWI/SNF) in response to inhibition of the AR signaling (Choi et al, 2022); (Han et al, 2022); (Nouruzi et al, 2022); (Bishop et al, 2017) ; (Cyrta et al, 2020). ...
Long non-coding RNAs (lncRNAs) represent vast and yet poorly characterized family of genes that can fine tune cellular plasticity, thereby allowing the emergence of aggressive therapy-resistant and metastatic cancers. Androgen deprivation therapies (ADT) are commonly used to treat prostate cancer by inactivating the Androgen Receptor (AR). However, castration-resistant prostate cancer (CRPC) with neuroendocrine subtypes (NEPC) often emerge. In this study, we explore the role of lncRNAs in response to androgen deprivation. Using a dynamic prostate cancer cell system mimicking the CRPC and NEPC onset, we identified 15 novel lncRNAs, with PROCA11 standing out as a first-choice candidate, being also highly abundant in high-risk prostate cancer tumors. This majorly nuclear lncRNA is expressed at low levels in androgen-dependent conditions of growth and strongly activated upon hormone withdrawal, preceding neuroendocrine genes and persisting at high levels in neuroendocrine cells. Extensive computational analysis of clinical data and functional studies in cells revealed PROCA11 association with basal-to-luminal transformation of the transcriptomic landscape and activation of metabolic and signaling pathways reminiscent of neurogenesis and of maintenance of AR signaling. We propose that PROCA11 is involved in the intricate circuits regulating cellular plasticity enabling cell survival and proliferation and emergence of the NE phenotype in response to ADT.
... Although the disease can develop de novo, it occurs primarily after androgen deprivation therapy (ADT) [3]. Treatment-induced NEPC (t-NEPC) has recently received attention 2 of 13 owing to the development of novel antiandrogen therapies However, although alterations in PTEN, TP53, RB1, and MYCN have been implicated in the development of NEPC. ...
Neuroendocrine prostate carcinoma (NEPC) accounts for less than 1% of prostate neo-plasms and has extremely poorer prognosis than the typical androgen receptor pathway-positive adenocarcinoma of the prostate (ARPC). However, very few cases in which de novo NEPC and APRC are diagnosed simultaneously in the same tissue have been reported. We report herein a 78-year-old man of de novo metastatic NEPC coexisting with ARPC treated at Ehime University Hospital. Visium CytAssist Spatial Gene Expression analysis (10× genetics) was performed using formalin-fixed, paraffin-embedded (FFPE) samples. The neuroendocrine signatures were upregulated in NEPC sites, and androgen receptor signatures were upregulated in ARPC sites. TP53, RB1, or PTEN and upregulation of the homologous recombination repair genes at NEPC sites were not downregulated. Urothelial carcinoma markers were not elevated. Meanwhile, Rbfox3 and SFRTM2 levels were downregulated while the levels of the fibrosis markers HGF, HMOX1, ELN, and GREM1 were upregulated in the tumor microenvironment of NEPC. In conclusion, the findings of spatial gene expression analysis in a patient with coexisting ARPC and de novo NEPC are reported. The accumulation of cases and basic data will help with the development of novel treatments for NEPC and improve the prognosis of patients with castration-resistant prostate cancer.
... Fifth, some cancer subtypes can transition from one histological diagnosis to another. For example, prostate and lung adenocarcinomas can acquire neuroendocrine histology in response to treatment with ADT [48] and EGFR inhibitors [49], respectively. It can be challenging to assign a precise diagnosis in situations where a tumor has a mixed or transitioning histology. ...
Introduction:
Cancers assume a variety of distinct histologies, and may originate from a myriad of sites including solid organs, hematopoietic cells, and connective tissue. Clinical decision-making based on consensus guidelines such as the National Comprehensive Cancer Network (NCCN) is often predicated on a specific histologic and anatomic diagnosis, supported by clinical features and pathologist interpretation of morphology and immunohistochemical (IHC) staining patterns. However, in patients with nonspecific morphologic and IHC findings-in addition to ambiguous clinical presentations such as recurrence versus new primary-a definitive diagnosis may not be possible, resulting in the patient being categorized as having a cancer of unknown primary (CUP). Therapeutic options and clinical outcomes are poor for patients with CUP, with a median survival of 8-11 months.
Methods:
Here, we describe and validate the Tempus Tumor Origin (Tempus TO) assay, an RNA-sequencing-based machine learning classifier capable of discriminating between 68 clinically relevant cancer subtypes. Model accuracy was assessed using primary and/or metastatic samples with known subtype.
Results:
We show that the Tempus TO model is 91% accurate when assessed on both a retrospectively held out cohort and a set of samples sequenced after model freeze that collectively contained 9210 total samples with known diagnoses. When evaluated on a cohort of CUPs, the model recapitulated established associations between genomic alterations and cancer subtype.
Discussion:
Combining diagnostic prediction tests (e.g., Tempus TO) with sequencing-based variant reporting (e.g., Tempus xT) may expand therapeutic options for patients with cancers of unknown primary or uncertain histology.
