Features Of Neuroendocrine Prostate Cancer Research Articles

Genetic and epigenetic features of neuroendocrine prostate cancer and their emerging applications.

Prostate cancer is the second most prevalent cancer in men globally. De novo neuroendocrine prostate cancer (NEPC) is uncommon at initial diagnosis, however, (treatment-induced) t-NEPC emerges in up to 25% of prostate adenocarcinoma (PRAD) cases treated with androgen deprivation, carrying a drastically poor prognosis. The transition from PRAD to t-NEPC is underpinned by several key genetic mutations; TP53, RB1, and MYCN are the main genes implicated, bearing similarities to other neuroendocrine tumours. A broad range of epigenetic alterations, such as aberrations in DNA methylation, histone post-translational modifications, and non-coding RNAs, may drive lineage plasticity from PRAD to t-NEPC. The clinical diagnosis of NEPC is hampered by a lack of accessible biomarkers; recent advances in liquid biopsy techniques assessing circulating tumour cells and ctDNA in NEPC suggest that the advent of non-invasive means of monitoring progression to NEPC is on the horizon. Such techniques are vital for NEPC management; diagnosis of t-NEPC is crucial for implementing effective treatment, and precision medicine will be integral to providing the best outcomes for patients.

Association of RB1 mutational status with overall genomic landscape in neuroendocrine prostate cancer (NEPC).

156 Background: NEPC is a high-grade aggressive form of prostate cancer. We queried whether RB1 mutation status would impact the genomic features of NEPC. We hypothesized that there would be differences in GA frequencies in RB1 mutated vs non mutated cases. Methods: From a series of 13,496 cases of clinically advanced PC, 415 (3.1%) histologically defined NEPC were sequenced using a hybrid capture-based FDA-approved clinical genomic profiling (CGP) assay to detect all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining 1-49% and high staining ≥50% expression. Results: 253 (61%) of NEPC feature GA in RB1 (RB1 mut+). This contrasts with a 5.8% frequency of RB1 GA in the non-NEPC (P <.0001). The RB1 mut+ NEPC featured a slightly greater number of driver GA/tumor than the RB1 mut- NEPC (5.1 vs 4.2). Age and TMPRSS2-ERG fusion frequency were similar between the groups. RB1 Mut- NEPC was associated with significantly higher amplifications (amp) and total GA in AR compared to RB1 mut+ NEPC. RB1 mut+ NEPC featured significantly greater frequency of PTEN GA. GA frequencies in targetable kinases and DNA repair GA including BRCA1/2 and ATM linked to PARP inhibitor (PARPi) response were similar in both groups. For potential immune-oncology (IO) biomarkers, RB1 Mut+ NEPC featured significantly greater frequency of low positive PD-L1 expression and lower frequencies of MDM2 and CDK12 GA. CD274 ( PD-L1) amplification, MSI-high status and cases with TMB ≥10 mut/Mb were very uncommon in both groups. Conclusions: In NEPC, the presence of RB1 mutation is associated with various GA that may have clinical relevance. Limitations include possible selection and confounding biases, and lack of clinical annotation. Further study of RB1 status as a guide of trial designs on therapy selection for men with NEPC is warranted.[Table: see text]

Clinical and Biological Features of Neuroendocrine Prostate Cancer.

Neuroendocrine prostate cancer (NEPC) is an aggressive histologic subtype of prostate cancer that most commonly arises in later stages of prostate cancer as a mechanism of treatment resistance. The poor prognosis of NEPC is attributed in part to late diagnosis and a lack of effective therapeutic agents. Here, we review the clinical and molecular features of NEPC based on recent studies and outline future strategies and directions. NEPC can arise "de novo" but most commonly develops as a result of lineage plasticity whereby prostate cancer cells adopt alternative lineage programs as a means to bypass therapy. Dependence on androgen receptor (AR) signaling is lost as tumors progress from a prostate adenocarcinoma to a NEPC histology, typically manifested by the downregulation of AR, PSA, and PSMA expression in tumors. Genomic analyses from patient biopsies combined with preclinical modeling have pointed to loss of tumor suppressors RB1 and TP53 as key facilitators of lineage plasticity. Activation of oncogenic drivers combined with significant epigenetic changes (e.g., EZH2 overexpression, DNA methylation) further drives tumor proliferation and expression of downstream neuronal and neuroendocrine lineage pathways controlled in part by pioneer and lineage determinant transcription factors (e.g., SOX2, ASCL1, BRN2). These biologic insights have provided a framework for the study of this subgroup of advanced prostate cancers and have started to provide rationale for the development of biomarker-driven therapeutic strategies. Further study of the dynamic process that leads to NEPC is required for the development of effective strategies to identify and treat patients developing lineage plasticity as a mechanism of treatment resistance.

Etoposide and topoisomerase II inhibition for aggressive prostate cancer: Data from a translational study.

BackgroundEtoposide phosphate (VP-16) is a topoisomerase 2 (TOP2) inhibitor that demonstrated activity in patients with metastatic castration-resistant prostate cancer (mCRPC). We investigated the sensitivity of prostate cancer (PCa) cells (LNCaP, 22Rv1, PC3, DU145, PDB and MDB) to VP-16 and the possible relationship between VP-16 activity and TOP2 expression. The activity of VP-16 was compared with that of docetaxel, enzalutamide and olaparib. The prevalence and clinical significance of TOP2 genetic and transcriptomic alterations was also explored in mCRPC. MethodsCell cultures and crystal violet cell proliferation assays were performed. Specific antibodies were used in western blots analyses of cell protein extracts. Datasets were analyzed in cBioportal. ResultsVP-16 was active in all PCa cell lines analyzed and demonstrated increased activity in PC3 and DU145 cells. VP-16 was more cytotoxic compared to the other treatments, except for LNCaP and 22Rv1, which were more sensitive to docetaxel. Maintenance of antiandrogen treatment in MDB and PDB increased sensitivity to VP-16, docetaxel and enzalutamide. TOP2A was found overexpressed in 22Rv1, DU145 and PC3, whereas TOP2B was overexpressed in 22Rv1 and PDB. In the mCRPC datasets analysis, TOP2A mRNA overexpression was associated with worse patients’ prognosis, with the molecular features of neuroendocrine prostate cancer (NEPC) and with lower androgen receptor (AR) score. Patients overexpressing TOP2A mRNA were more likely to harbor RB1 loss. ConclusionsSpecific subpopulations of patients with aggressive variant prostate cancer (AVPC) could benefit from VP-16 treatment. TOP2A overexpression, rather than TOP2B, might be a good biomarker to predict response to VP-16.

Clinical features of neuroendocrine prostate cancer

BackgroundNeuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may arise de novo or in patients previously treated with hormonal therapies for prostate adenocarcinoma as a mechanism of resistance. Despite being important to recognise, the clinical features of NEPC are poorly defined and could help guide when to perform a biopsy to look for NEPC histologic transformation. MethodsWe reviewed baseline, treatment and outcome data of 87 patients with metastatic prostate cancer and tumour biopsy confirming NEPC histology. Forty-seven (54.0%) NEPC cases presented de novo, and 40 (46.0%) were therapy-related (t-NEPC). Thirty-six (41.4%) were classified as pure small-cell carcinoma, and 51 (58.6%) demonstrated mixed features with both small-cell carcinoma and adenocarcinoma present. Genomic data were available for 47 patients. ResultsThe median age at time of NEPC was 68.1 years, median prostate-specific antigen (PSA) was 1.20 ng/ml (0.14 ng/mL small-cell carcinoma, 1.55 ng/mL mixed carcinoma) and sites of metastases included bone (72.6%), lymph node (47.0%), and viscera (65.5%). Median time from adenocarcinoma to t-NEPC diagnosis was 39.7 months (range, 24.5–93.8) with a median of two lines of prior systemic therapy. Platinum chemotherapy was used to treat 57.5% of patients, with a median progression-free survival of 3.9 months. Small-cell carcinoma was associated with worse overall survival (OS) than mixed histology (8.9 months from NEPC diagnosis versus 26.1 months, P < 0.001). Median OS of de novo NEPC was shorter than that of t-NEPC (16.8 months from prostate cancer diagnosis versus 53.5 months, P = 0.043). An average PSA rise per month of ≤0.7 ng/ml before t-NEPC; elevated lactate dehydrogenase levels, RB1 and TP53 loss and liver metastases were poor prognostic features. ConclusionsWe describe the clinical features of a cohort of patients with NEPC. These characteristics may inform future diagnostic strategies.

Abstract 3017: Role of long noncoding RNA H19 in driving enzalutamide resistant neuroendocrine prostate cancer

Abstract INTRODUCTION: Approximately one-fourth of the prostate cancer (PCa) patients relapsing androgen deprivation therapy (ADT) have been shown to develop neuroendocrine prostate cancer (NEPC). One of the primary mechanisms attributed to this resistance is the lineage switching of epithelial cells to neuroendocrine (NE) phenotype making them independent of androgen receptor (AR) pathways for survival. Molecular basis essential to this lineage switch requires further elucidation. Thus, we aim to understand key mechanistic pathways that drive the development and maintenance of NEPC, and to investigate if the inhibition of pathway can re-sensitize to ADT in NEPC. METHODS: Bioinformatics analysis was performed with existing databases to compare prostate adenocarcinoma (PCA) vs NEPC. Molecular features of NEPC have been shown to depict RB1 loss in 70-90% and TP53 loss in 56-67% of the cases. Thus, we established prostate organoid cultures from P53fl/fl/Rbfl/fl mouse and infected them with Cre-lentivirus for combined loss of TP53/Rb1. Various PCA and NEPC cell lines and patient derived organoids were used to study the role of the long non-coding RNA H19 in NEPC. Organoid growth were assessed with Incucyte and invasive capacity was measured by Matrigel invasion assay. RESULTS: Bioinformatic analysis of exisiting human PCa data sets demonstrate that H19 is one of the most highly expressed genes in NEPC and parallels the expression of NE markers. Indeed, we confirmed that H19 expression was high in various NEPC cell lines and NE patient derived organoids. H19 was also found to be markedly induced in mouse prostate organoids and LNCaP cells after TP53/Rb1 loss. Importantly, overexpression of H19 induced NE genes while suppressing the genes involved in AR signaling in LNCaP and primary PCa patient derived organoids and inversely, knockdown (KD) of H19 in LNCaP and mouse prostate organoids with TP53/Rb1 loss reduced the expression of NE gene. Interestingly, the KD of H19 in these cells re-induced the luminal phenotype, consequently restoring their sensitivity to ADT. These findings strongly implicate H19 in driving the NE lineage switch. The KD of H19 in these organoids led to a regression of tumor growth and invasiveness, suggesting H19 is required in malignant states. H19 KD decreases stem cell genes (SOX2, OCT4) via methylation of their promoters, and levels of EZH2, which methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3 and represses transcription of the target genes. H3K27me3 levels, which are high in NEPC, was reduced in the H19 KD, suggesting H19 works in an epigenetic regulation to induce NEPC phenotype. CONCLUSION: These data highlight H19 as a novel regulator in controlling the lineage switch to NEPC, tumor growth, and the sensitivity to hormone blockade, suggesting that H19 regulation will be important for developing treatments specifically aimed for this highly aggressive form of prostate cancer. Citation Format: Neha Singh, Virginie Olive, Ritu Pandey, Jin Song, Jeremiah Bearrs, Sathish K. Padi, Koichi Okumura, Andrew S. Kraft. Role of long noncoding RNA H19 in driving enzalutamide resistant neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3017.

Clinical experience with PSMA-Actinium-225 (Ac-225) radioligand therapy (RLT) in end-stage metastatic castration-resistant prostate cancer (mCRPC) patients.

344 Background: Prostate-specific membrane antigen (PSMA) is an ideal target for RLT in mCRPC patients (pts). Alpha-emitting radioisotope Actinium-225 (Ac-225) may be more efficacious than beta-emitting Lutetium-177, due to higher rates of double-strand DNA breaks in prostate cancer cells, with less tissue penetration and minimal bystander effects in PSMA-negative cells. Limited data is available on the clinical efficacy and side effects of PSMA-Ac-225 RLT in mCRPC pts. Here we describe our clinical experience so far. Methods: Between February 2016 and October 2017, 11 pts underwent PSMA-Ac-225 RLT in Heidelberg, Germany. Prostate-specific antigen (PSA) responses were measured every two weeks. Pts underwent PSMA PET/CT prior to and after RLT. Consenting pts had tissue and blood collected for translational biomarker studies, including targeted-next generation sequencing and whole genome sequencing to discover biomarkers and mechanisms of RLT resistance. In addition, pts received structured questionnaires on quality of life and xerostomia evaluation. Results: All pts were heavily pre-treated, with a median of four therapies prior to PSMA-Ac-225 RLT. Pts underwent a median of three RLT cycles (range 1-4 cycles) of median 8 MBq (range 6-10 MBq). Five pts (45%) had died at time of analysis. Median overall survival since start of RLT was 12.6 months (95% CI 5.0-20.1). Median baseline PSA was 878 µg/L (range 6-2249). Eight of eleven pts had &gt; 50% PSA response, with median change in PSA reduction of 87%. Six pts were evaluable according to PCWG3 criteria with 5/6 (83%) pts showing partial responses, and one patient with stable disease following RLT. No grade 3-4 hematologic toxicity occurred. Grade 2-3 xerostomia was mentioned by all pts. Pts with features of neuro-endocrine prostate cancer (NEPC) showed less response to RLT, with blood-based NEPC biomarkers increasing during RLT. Conclusions: PSMA-Ac-225 RLT resulted in remarkable clinical, biochemical and radiological responses in end-stage mCRPC pts, and may be considered a promising therapy for mCRPC pts.

Abstract LB-018: Defining a molecular subclass of treatment-resistant prostate cancer

Abstract Background: A subset of advanced prostate cancers can progress from an androgen driven state to androgen receptor (AR) independence, often associated with low or absent AR expression and extensive neuroendocrine differentiation. Once neuroendocrine prostate cancer (NEPC) develops, patients typically demonstrate an aggressive clinical course, resistance to AR therapies, and poor overall survival. Early diagnosis is important but remains challenging as the clinical and pathologic features associate with AR independence and NEPC are currently poorly defined. Methods: To address this gap in knowledge, we performed whole exome sequencing (WES) of 124 metastatic tumors from 81 patients including 35 with morphologic features of NEPC. Patients with serial or synchronous samples were included to characterize disease heterogeneity and the transition from adenocarcinoma to NEPC. Immunohistochemistry was performed for neuroendocrine markers and AR in all cases. Computational analysis of clonality and allele specific quantification of copy number were performed using CLONET. Expression profiling (RNA-seq and/or quantitative assessment of a targeted panel of AR signaling genes by Nanostring) and DNA methylation were evaluated in the context of genomic changes. Results: The mutational landscape of NEPC and castration resistant prostate cancer (CRPC) did not differ significantly by rate of non-synonymous mutations or copy number burden (on average &amp;gt;40% of the genome was aberrant), and polyploidy was frequently detected together with common allelic imbalances. Comparative analysis at the DNA and mRNA level identified significant decrease in AR signaling in NEPC and a range of AR signaling in CRPC, enrichment of copy number losses (including RB1 and multiple genes on 16q) in NEPC, and focal high level AR amplification in CRPC in contrast to NEPCs (p-val = 0.0007). DNA allele specific analysis of multi-sample cases including patient matched adenocarcinoma-NEPC tumors suggested diverse genomic state of key lesions including aberrations in MYCN and CDKN1B. Conclusions: This is largest study to date focused on the molecular landscape of the NEPC resistance phenotype. NEPC is characterized by a molecular profile defined by distinct genomic alterations and decreased AR signaling. A subgroup of CRPC demonstrates lower AR signaling and molecular overlap with NEPC. This study supports clonal evolution of prostate adenocarcinoma to NEPC, provides new insight into NEPC biology and disease heterogeneity, and may aid in the detection of AR independence and emergence of the NEPC subclass of treatment resistance. Citation Format: Himisha Beltran, Davide Prandi, Juan Miguel Mosquera, Eugenia Giannopoulou, Loredana Puca, Clarisse Marotz, David M. Nanus, Scott T. Tagawa, Olivier Elemento, Eliezer Van Allen, Andrea Sboner, Levi Garraway, Mark A. Rubin, Francesca Demichelis. Defining a molecular subclass of treatment-resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-018. doi:10.1158/1538-7445.AM2015-LB-018