Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer.
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ABSTRACT:
SUBMITTER: Beltran H
PROVIDER: S-EPMC4777652 | biostudies-literature | 2016 Mar
REPOSITORIES: biostudies-literature
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Project description:Intratumor heterogeneity is a key driver for local relapse and treatment failure. Thus, using multifocal prostate cancer as a model to investigate tumor inter-clonal relationships and tumor evolution could aid in our understanding of drug resistance. Previous studies discovered genomic alterations by comparing hormone-sensitive prostate cancer (HSPC) with castration-resistant prostate cancer (CRPC) in large cohorts. However, most studies did not sequentially sample tumors from the same patient. In our study, we performed whole-exome sequencing (WES) on 14 specimens from five locally relapsed patients before and after androgen-deprivation therapy. We described the landscape of genomic alterations before and after treatment and identified critical driver events that could have contributed to the evolution of CRPC. In addition to confirming known cancer genes such as TP53 and CDK12, we also identified new candidate genes that may play a role in the progression of prostate cancer, including MYO15A, CHD6 and LZTR1. At copy number alteration (CNA) level, gain of 8q24.13-8q24.3 was observed in 60% of patients and was the most commonly altered locus in both HSPC and CRPC tumors. Finally, utilizing phylogenetic reconstruction, we explored the clonal progression pattern from HSPC to CRPC in each patient. Our findings highlight the complex and heterogeneous mechanisms underlying the development of drug resistance, and underscore the potential value of monitoring tumor clonal architectures during disease progression in a clinical setting.
| S-EPMC8681025 | biostudies-literature
Project description:Therapy-induced neuroendocrine prostate cancer (NEPC), an extremely aggressive variant of castration-resistant prostate cancer (CRPC), is increasing in incidence with the widespread use of highly potent androgen receptor (AR)-pathway inhibitors (APIs) such as Enzalutamide (ENZ) and Abiraterone and arises via a reversible trans-differentiation process, referred to as neuroendocrine differentiation (NED). The molecular basis of NED is not completely understood leading to a lack of effective molecular markers for its diagnosis. Here, we demonstrate for the first time, that lineage switching to NE states is accompanied by key miRNA alterations including downregulation of miR-106a~363 cluster and upregulation of miR-301a and miR-375. To systematically investigate the key miRNAs alterations driving therapy-induced NED, we performed small RNA-NGS in a retrospective cohort of human metastatic CRPC clinical samples + PDX models with adenocarcinoma features (CRPC-adeno) vs those with neuroendocrine features (CRPC-NE). Further, with the application of machine learning algorithms to sequencing data, we trained a 'miRNA classifier' that could robustly classify 'CRPC-NE' from 'CRPC-Adeno' cases. The performance of classifier was validated in an additional cohort of mCRPC patients and publicly available PCa cohorts. Importantly, we demonstrate that miR-106a~363 cluster pleiotropically regulate cardinal nodal proteins instrumental in driving NEPC including Aurora Kinase A, N-Myc, E2F1 and STAT3. Our study has important clinical implications and transformative potential as our 'miRNA classifier' can be used as a molecular tool to stratify mCRPC patients into those with/without NED and guide treatment decisions. Further, we identify novel miRNA NED drivers that can be exploited for NEPC therapeutic targeting.
| S-EPMC7718386 | biostudies-literature
Project description:Loss of androgen receptor (AR) signaling dependence occurs in approximately 15%-20% of advanced treatment-resistant prostate cancers, and this may manifest clinically as transformation from a prostate adenocarcinoma histology to a castration-resistant neuroendocrine prostate cancer (CRPC-NE). The diagnosis of CRPC-NE currently relies on a metastatic tumor biopsy, which is invasive for patients and sometimes challenging to diagnose due to morphologic heterogeneity. By studying whole-exome sequencing and whole-genome bisulfite sequencing of cell free DNA (cfDNA) and of matched metastatic tumor biopsies from patients with metastatic prostate adenocarcinoma and CRPC-NE, we identified CRPC-NE features detectable in the circulation. Overall, there was markedly higher concordance between cfDNA and biopsy tissue genomic alterations in patients with CRPC-NE compared with castration-resistant adenocarcinoma, supporting greater intraindividual genomic consistency across metastases. Allele-specific copy number and serial sampling analyses allowed for the detection and tracking of clonal and subclonal tumor cell populations. cfDNA methylation was indicative of circulating tumor content fraction, reflective of methylation patterns observed in biopsy tissues, and was capable of detecting CRPC-NE-associated epigenetic changes (e.g., hypermethylation of ASXL3 and SPDEF; hypomethylation of INSM1 and CDH2). A targeted set combining genomic (TP53, RB1, CYLD, AR) and epigenomic (hypo- and hypermethylation of 20 differential sites) alterations applied to ctDNA was capable of identifying patients with CRPC-NE.
| S-EPMC7108892 | biostudies-literature
Project description:After the introduction of prostate cancer screening with the prostate-specific antigen (PSA) test, we have witnessed a dramatic stage migration. As a result, an increasing number of patients are diagnosed at earlier stages and receive local treatments including surgery or radiation. When these local treatments fail by the definition of increasing PSA levels, patients are usually treated with androgen-deprivation therapy. A fraction of these patients will finally reach a state of castration-resistant prostate cancer (CRPC) even without radiological evidence of metastasis, which is referred to as nonmetastatic CRPC (NM-CRPC). Most men with advanced or metastatic prostate cancer initially respond to various types of androgen ablation, but a considerable portion of them eventually progress to NM-CRPC. Among patients with NM-CPRC, about one-third will develop bone metastasis within 2 years. In these patients, PSA kinetics is the most powerful indicator of progression and is usually used to trigger further imaging studies and enrollment in clinical trials. Although CRPC remains largely driven by the androgen receptor, the benefit of second-line hormonal manipulations, including first-generation antiandrogens, adrenal synthesis inhibitors, and steroids, has not been investigated in men with NM-CRPC. To date, denosumab is the only agent that has been shown to delay the onset of bone metastasis. However, overall survival did not differ. In treating NM-CRPC patients, physicians should recognize the heterogeneity of the disease and acknowledge that the recently approved second-line treatments have been studied only in advanced stages of the disease.
| S-EPMC3956942 | biostudies-other
Project description:Conventional treatment of prostate cancer (PCa) uses androgen-deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling-driven tumor progression. ADT-induced PCa recurrence may progress to an AR-negative phenotype with neuroendocrine (NE) histologic features, which are associated with metabolic disturbances and poor prognoses. However, the metabolic pathways that regulate NE differentiation (NED) in PCa remain unclear. Herein, we show a regulatory mechanism in NED-associated metabolism dysfunction induced by ADT, whereby overexpression of pyruvate kinase L/R (PKLR) mediates oxidative stress through upregulation of reactive oxygen species modulator 1 (ROMO1), thereby promoting NED and aggressiveness. ADT mediates the nuclear translocation of PKLR, which binds to the MYCN/MAX complex to upregulate ROMO1 and NE-related genes, leading to altered mitochondrial function and NED of PCa. Targeting nuclear PKLR/MYCN using bromodomain and extra-terminal motif (BET) inhibitors has the potential to reduce PKLR/MYCN-driven NED. Abundant ROMO1 in serum samples may provide prognostic information in patients with ADT. Our results suggest that ADT resistance leads to upregulation of PKLR/MYCN/ROMO1 signaling, which may drive metabolic reprogramming and NED in PCa. We further show that increased abundance of serum ROMO1 may be associated with the development of NE-like PCa.
| S-EPMC10060381 | biostudies-literature
Project description:There is evidence that cancer stem-like cells (CSC) and neuroendocrine behavior play critical roles in the pathogenesis and clinical course of metastatic castration-resistant prostate cancer (m-CRPC). However, there is limited mechanistic understanding of how CSC and neuroendocrine phenotypes impact the development of m-CRPC. In this study, we explored the role of the intracellular chemokine CXCL12γ in CSC induction and neuroendocrine differentiation and its impact on m-CRPC. CXCL12γ expression was detected in small-cell carcinoma of metastatic tissues and circulating tumor cells from m-CRPC patients and in prostate cancer cells displaying an neuroendocrine phenotype. Mechanistic investigations demonstrated that overexpression of CXCL12γ induced CSC and neuroendocrine phenotypes in prostate cancer cells through CXCR4-mediated PKCα/NFκB signaling, which promoted prostate tumor outgrowth, metastasis, and chemoresistance in vivo Together, our results establish a significant function for CXCL12γ in m-CRPC development and suggest it as a candidate therapeutic target to control aggressive disease.Significance: Expression of CXCL12γ induces the expression of a cancer stem cell and neuroendocrine phenotypes, resulting in the development of aggressive m-CRPC. Cancer Res; 78(8); 2026-39. ©2018 AACR.
| S-EPMC6324566 | biostudies-literature
Project description:PURPOSE:The molecular targets for castration-resistant prostate cancer (CRPC) are unknown because the disease inevitably recurs, and therapeutic approaches for patients with CRPC remain less well understood. We sought to investigate regulatory mechanisms that result in increased therapeutic resistance, which is associated with neuroendocrine differentiation of prostate cancer and linked to dysregulation of the androgen-responsive pathway. EXPERIMENTAL DESIGN:The underlying intracellular mechanism that sustains the oncogenic network involved in neuroendocrine differentiation and therapeutic resistance of prostate cancer was evaluated to investigate and identify effectors. Multiple sets of samples with prostate adenocarcinomas and CRPC were assessed via IHC and other assays. RESULTS:We demonstrated that leukemia inhibitory factor (LIF) was induced by androgen deprivation therapy (ADT) and was upregulated by ZBTB46 in prostate cancer to promote CRPC and neuroendocrine differentiation. LIF was found to be induced in patients with prostate cancer after ADT and was associated with enriched nuclear ZBTB46 staining in high-grade prostate tumors. In prostate cancer cells, high ZBTB46 output was responsible for the activation of LIF-STAT3 signaling and neuroendocrine-like features. The abundance of LIF was mediated by ADT-induced ZBTB46 through a physical interaction with the regulatory sequence of LIF. Analysis of serum from patients showed that cases of higher tumor grade and metastatic prostate cancer exhibited higher LIF titers. CONCLUSIONS:Our findings suggest that LIF is a potent serum biomarker for diagnosing advanced prostate cancer and that targeting the ZBTB46-LIF axis may therefore inhibit CRPC development and neuroendocrine differentiation after ADT.
| S-EPMC7168873 | biostudies-literature
Project description:IntroductionTreatment strategy for castration-resistant prostate cancer with neuroendocrine differentiation after radiation therapy has not been established.Case presentationWe described a case of castration-resistant prostate cancer with neuroendocrine differentiation after initial external beam radiotherapy followed by salvage androgen deprivation therapy. Magnetic resonance imaging detected recurrence of a suspicious lesion in the left lobe of the prostate, although the prostate-specific antigen level was <0.2 ng/mL. Transperineal prostate saturation needle biopsy detected adenocarcinoma with neuroendocrine differentiation. The patient underwent salvage focal brachytherapy and had a prostate-specific antigen progression-free survival of 20 months with no obvious adverse events. No recurrence has been detected on magnetic resonance imaging for 18 months.ConclusionSalvage focal brachytherapy for prostate cancer after external beam radiotherapy can be one of the treatment strategies for local recurrence of castration-resistant prostate cancer with neuroendocrine differentiation.
| S-EPMC9249630 | biostudies-literature
Project description:BackgroundNowadays, the incidence rate of advanced and metastatic prostate cancer at the first time of diagnosis grows higher in China yearly. At present, androgen deprivation therapy (ADT) is the primary treatment of advanced prostate cancer. However, after several years of ADT, most patients will ultimately progress to castration-resistant prostate cancer (CRPC). Previous studies mainly focus on Caucasian and very few on East Asian patients.MethodsIn this study, the pre- and post-ADT tumor samples were collected from five Chinese patients with advanced prostate cancer. The whole-exome sequencing, tumor heterogeneity, and clonal evolution pattern were analyzed.ResultsThe results showed that the gene mutation pattern and heterogeneity changed significantly after androgen deprivation therapy. Tumor Mutational Burden (TMB) and Copy Number Alteration (CNA) were substantially reduced in the post-treatment group, but the Mutant-allele tumor heterogeneity (MATH), Socio-Demographic Index (SDI), Intratumor heterogeneity (ITH), and weighted Genome Instability Index (wGII) had no significant difference. According to the clone types and characteristics, the presence of main clones in five pre-and post-treatment samples, the clonal evolution pattern can be further classified into two sub-groups (the Homogeneous origin clonal model or the Heterogeneous origin clonal model). The Progression-free survival (PFS) of the patients with the "Homogeneous origin clonal model" was shorter than the "Heterogeneous origin clonal model". The longer PFS might relate to MUC7 and MUC5B mutations repaired. ZNF91 mutation might be responsible for resistance to ADT resistance.ConclusionOur findings revealed potential genetic regulators to predict the castration resistance and provide insights into the castration resistance processes in advanced prostate cancer. The crosstalk between clonal evolution patterns and tumor microenvironment may also play a role in castration resistance. A multicenter-research including larger populations with different background are needed to confirm our conclusion in the future.
| S-EPMC10510184 | biostudies-literature
Project description:Neuroendocrine differentiation of prostate cancer (NEDPC) includes de novo presentation and secondary to epigenetic changes, referred as therapy-induced neuroendocrine prostate cancer (t-NEPC). Molecular imaging with prostate-specific membrane antigen (PSMA) and somatostatin analogues positron emission tomography (PET/CT) in NEDPC have not been validated. 18F-FDG (fluorodeoxyglucose) PET/CT has numerous limitations in prostate cancer (PCa) and the utility in NEDPC has only been reported in a few series of cases. The objective of this study is to compare the lesions detection rate of the three radiotracers in metastatic t-NEPC patients. (1) Material and Methods: Retrospective evaluation of patients with prostate adenocarcinoma treated with androgen deprivation therapy, chemotherapy, a novel androgen receptor pathway inhibitor or a combination of them and a second tumour biopsy confirming t-NEPC was made. All patients underwent 18F PSMA-1007, 18F AlF-NOTA-Octreotide, and 18F-FDG PET/CT. Evaluation of positive lesions was determined and SUVmax of each radiotracer was estimated and correlated with computer tomography (CT) findings. (2) Results: A total of eight patients were included. The mean time from diagnosis of prostate adenocarcinoma to t-NEPC was 28.2 months, with a mean serum specific prostate antigen (PSA) of 16.6 ng/dl at the time of NEPC diagnosis. All patients were treated with antiandrogen therapy and 87.5% with chemotherapy. A total of 273 lesions were identified by CT from which 182 were detected by 18F-FDG PET/CT, 174 lesions by 18F PSMA-1007, and 59 by 18F AlF-NOTA-Octreotide. An interpatient analysis of the lesions was performed and dual tracer 18F-FDG PET/CT and 18F PSMA-1007 PET/CT detected a total of 270/273 lesions (98.9%). (3) Conclusions: NEDPC patients demonstrated wide inter and intrapatient molecular imaging heterogeneity within the three radiotracers. 18F-FDG detected most lesions in t-NEPC among all radiotracers, especially in visceral sites; 18F PSMA-1007 detected more bone lesions. 18F AlF-NOTA-Octreotide showed no significant utility.
| S-EPMC9221809 | biostudies-literature