Therapy considerations in neuroendocrine prostate cancer: what next?

Endocrine Related Cancer ◽

10.1530/erc-21-0140 ◽

2021 ◽

Author(s):

Himisha Beltran ◽

Francesca Demichelis

Keyword(s):

Prostate Cancer ◽

Treatment Resistance ◽

Prostate Adenocarcinoma ◽

Small Cell ◽

Small Cell Neuroendocrine Carcinoma ◽

Course Of Disease ◽

Molecular Features ◽

Neuroendocrine Prostate Cancer ◽

Androgen Receptor Activity ◽

Cancer Phenotype

Lineage plasticity and histologic transformation to small cell neuroendocrine prostate cancer (NEPC) is an increasingly recognized mechanism of treatment resistance in advanced prostate cancer. This is associated with aggressive clinical features and poor prognosis. Recent work has identified genomic, epigenomic, and transcriptome changes that distinguish NEPC from prostate adenocarcinoma, pointing to new mechanisms and therapeutic targets. Treatment-related NEPC arises clonally from prostate adenocarcinoma during the course of disease progression, retaining early genomic events and acquiring new molecular features that lead to tumor proliferation independent of androgen receptor activity, and ultimately demonstrating a lineage switch from a luminal prostate cancer phenotype to a small cell neuroendocrine carcinoma. Identifying the subset of prostate tumors most vulnerable to lineage plasticity and developing strategies for earlier detection and intervention for patients with NEPC may ultimately improve prognosis. Clinical trials focused on drug targeting of the lineage plasticity process and/or NEPC will require careful patient selection. Here, we review emerging targets and discuss biomarker considerations that may be informative for the design of future clinical studies.

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Molecular and Functional Links between Neurodevelopmental Processes and Treatment-Induced Neuroendocrine Plasticity in Prostate Cancer Progression

Cancers ◽

10.3390/cancers13040692 ◽

2021 ◽

Vol 13 (4) ◽

pp. 692

Author(s):

Roosa Kaarijärvi ◽

Heidi Kaljunen ◽

Kirsi Ketola

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Treatment Resistance ◽

Research Field ◽

Phenotypic Change ◽

Prostate Cancer Progression ◽

Castration Resistant Prostate Cancer ◽

Treatment Resistant ◽

Molecular Features ◽

Neuroendocrine Prostate Cancer

Neuroendocrine plasticity and treatment-induced neuroendocrine phenotypes have recently been proposed as important resistance mechanisms underlying prostate cancer progression. Treatment-induced neuroendocrine prostate cancer (t-NEPC) is highly aggressive subtype of castration-resistant prostate cancer which develops for one fifth of patients under prolonged androgen deprivation. In recent years, understanding of molecular features and phenotypic changes in neuroendocrine plasticity has been grown. However, there are still fundamental questions to be answered in this emerging research field, for example, why and how do the prostate cancer treatment-resistant cells acquire neuron-like phenotype. The advantages of the phenotypic change and the role of tumor microenvironment in controlling cellular plasticity and in the emergence of treatment-resistant aggressive forms of prostate cancer is mostly unknown. Here, we discuss the molecular and functional links between neurodevelopmental processes and treatment-induced neuroendocrine plasticity in prostate cancer progression and treatment resistance. We provide an overview of the emergence of neurite-like cells in neuroendocrine prostate cancer cells and whether the reported t-NEPC pathways and proteins relate to neurodevelopmental processes like neurogenesis and axonogenesis during the development of treatment resistance. We also discuss emerging novel therapeutic targets modulating neuroendocrine plasticity.

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Circulating tumor cell heterogeneity in neuroendocrine prostate cancer by single cell copy number analysis

npj Precision Oncology ◽

10.1038/s41698-021-00211-1 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Vincenza Conteduca ◽

Sheng-Yu Ku ◽

Luisa Fernandez ◽

Angel Dago-Rodriquez ◽

Jerry Lee ◽

...

Keyword(s):

Prostate Cancer ◽

Single Cell ◽

De Novo ◽

Genomic Analysis ◽

Treatment Resistance ◽

Circulating Tumor Cell ◽

Prostate Adenocarcinoma ◽

Neuroendocrine Prostate Cancer ◽

Patient Heterogeneity ◽

Tumor Cell Heterogeneity

AbstractNeuroendocrine prostate cancer is an aggressive variant of prostate cancer that may arise de novo or develop from pre-existing prostate adenocarcinoma as a mechanism of treatment resistance. The combined loss of tumor suppressors RB1, TP53, and PTEN are frequent in NEPC but also present in a subset of prostate adenocarcinomas. Most clinical and preclinical studies support a trans-differentiation process, whereby NEPC arises clonally from a prostate adenocarcinoma precursor during the course of treatment resistance. Here we highlight a case of NEPC with significant intra-patient heterogeneity observed across metastases. We further demonstrate how single-cell genomic analysis of circulating tumor cells combined with a phenotypic evaluation of cellular diversity can be considered as a window into tumor heterogeneity in patients with advanced prostate cancer.

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Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer

Science Translational Medicine ◽

10.1126/scitranslmed.aav0891 ◽

2019 ◽

Vol 11 (484) ◽

pp. eaav0891 ◽

Cited By ~ 23

Author(s):

Loredana Puca ◽

Katie Gavyert ◽

Verena Sailer ◽

Vincenza Conteduca ◽

Etienne Dardenne ◽

...

Keyword(s):

Prostate Cancer ◽

Phase 1 ◽

Treatment Resistance ◽

Small Cell ◽

Small Cell Lung ◽

Antibody Drug Conjugate ◽

Neuroendocrine Marker ◽

Castration Resistant ◽

Neuroendocrine Prostate Cancer ◽

Benign Prostate

Histologic transformation to small cell neuroendocrine prostate cancer occurs in a subset of patients with advanced prostate cancer as a mechanism of treatment resistance. Rovalpituzumab tesirine (SC16LD6.5) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) and was initially developed for small cell lung cancer. We found that DLL3 is expressed in most of the castration-resistant neuroendocrine prostate cancer (CRPC-NE) (36 of 47, 76.6%) and in a subset of castration-resistant prostate adenocarcinomas (7 of 56, 12.5%). It shows minimal to no expression in localized prostate cancer (1 of 194) and benign prostate (0 of 103). DLL3 expression correlates with neuroendocrine marker expression,RB1loss, and aggressive clinical features. DLL3 in circulating tumor cells was concordant with matched metastatic biopsy (87%). Treatment of DLL3-expressing prostate cancer xenografts with a single dose of SC16LD6.5 resulted in complete and durable responses, whereas DLL3-negative models were insensitive. We highlight a patient with neuroendocrine prostate cancer with a meaningful clinical and radiologic response to SC16LD6.5 when treated on a phase 1 trial. Overall, our findings indicate that DLL3 is preferentially expressed in CRPC-NE and provide rationale for targeting DLL3 in patients with DLL3-positive metastatic prostate cancer.

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Multi-Omics Analyses Detail Metabolic Reprogramming in Lipids, Carnitines, and Use of Glycolytic Intermediates between Prostate Small Cell Neuroendocrine Carcinoma and Prostate Adenocarcinoma

Metabolites ◽

10.3390/metabo9050082 ◽

2019 ◽

Vol 9 (5) ◽

pp. 82 ◽

Cited By ~ 4

Author(s):

Bei Gao ◽

Hui-Wen Lue ◽

Jennifer Podolak ◽

Sili Fan ◽

Ying Zhang ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Lines ◽

Neuroendocrine Carcinoma ◽

Prostate Adenocarcinoma ◽

Small Cell ◽

Gene Set Enrichment Analysis ◽

Metabolic Reprogramming ◽

Small Cell Neuroendocrine Carcinoma ◽

Gene Sets ◽

Glycolytic Intermediates

As the most common cancer in men, prostate cancer is molecularly heterogeneous. Contributing to this heterogeneity are the poorly understood metabolic adaptations of the two main types of prostate cancer, i.e., adenocarcinoma and small cell neuroendocrine carcinoma (SCNC), the latter being more aggressive and lethal. Using transcriptomics, untargeted metabolomics and lipidomics profiling on LASCPC-01 (prostate SCNC) and LNCAP (prostate adenocarcinoma) cell lines, we found significant differences in the cellular phenotypes of the two cell lines. Gene set enrichment analysis on the transcriptomics data showed 62 gene sets were upregulated in LASCPC-01, while 112 gene sets were upregulated in LNCAP. ChemRICH analysis on metabolomics and lipidomics data revealed a total of 25 metabolite clusters were significantly different. LASCPC-01 exhibited a higher glycolytic activity and lower levels of triglycerides, while the LNCAP cell line showed increases in one-carbon metabolism as an exit route of glycolytic intermediates and a decrease in carnitine, a mitochondrial lipid transporter. Our findings pinpoint differences in prostate neuroendocrine carcinoma versus prostate adenocarcinoma that could lead to new therapeutic targets in each type.

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Models of neuroendocrine prostate cancer

Endocrine Related Cancer ◽

10.1530/erc-14-0393 ◽

2014 ◽

Vol 22 (1) ◽

pp. R33-R49 ◽

Cited By ~ 29

Author(s):

Lisa D Berman-Booty ◽

Karen E Knudsen

Keyword(s):

Prostate Cancer ◽

Small Cell ◽

Genetically Engineered ◽

Cancer Death ◽

Xenograft Tumor ◽

Small Cell Neuroendocrine Carcinoma ◽

Genetically Engineered Mouse Models ◽

Aggressive Form ◽

Neuroendocrine Prostate Cancer ◽

The Usa

Prostate cancer remains the second leading cause of cancer death in men in the USA and most western countries. Prostatic acinar adenocarcinoma is the most commonly diagnosed form of prostate cancer. Small-cell neuroendocrine carcinoma is less frequently identified at the time of initial diagnosis, but this highly aggressive form of prostate cancer is increasingly observed in patients who have failed first- and second-line hormone therapy. Thus, developing and exploring models of neuroendocrine prostate cancer (NePC) are of increasing importance. This review examines the relevant xenograft tumor and genetically engineered mouse models of NePC, with the aim of addressing salient features and clinical relevance.

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Intratibial implantation of tumor cells v1

10.17504/protocols.io.bvrsn56e ◽

2021 ◽

Author(s):

Shubhangi Agarwal ◽

donna.peehl not provided ◽

Renuka Sriram

Keyword(s):

Prostate Cancer ◽

Cancer Patient ◽

Metastatic Prostate Cancer ◽

Prostate Cancer Patient ◽

Tumor Cell Line ◽

Small Cell ◽

Response To Therapy ◽

Tumor Characteristics ◽

Patient Derived Xenograft ◽

Neuroendocrine Prostate Cancer

This protocol describes the steps required for the successful implantation of small cell neuroendocrine prostate cancer patient-derived xenograft (PDX) cells in the bone. Bone is one of the most common sites for the development of metastatic prostate cancer and its study is important for evaluating the tumor characteristics and response to therapy. This protocol can be used for the implantation of any tumor cell line in the bone.

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Role of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity

Nature Communications ◽

10.1038/s41467-020-19328-1 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Joanna Cyrta ◽

Anke Augspach ◽

Maria Rosaria De Filippo ◽

Davide Prandi ◽

Phillip Thienger ◽

...

Keyword(s):

Prostate Cancer ◽

Chromatin Remodeling ◽

Hormonal Treatment ◽

Prostate Adenocarcinoma ◽

Aggressive Disease ◽

Chromatin Remodeling Complex ◽

Large Patient ◽

Neuroendocrine Prostate Cancer ◽

Specific Factors

Abstract Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in around 10–20% of these patients is lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data point to a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may also be relevant for other solid tumors.

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Neuroendocrine Differentiation of Prostate Cancer—An Intriguing Example of Tumor Evolution at Play

Cancers ◽

10.3390/cancers11101405 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1405 ◽

Cited By ~ 11

Author(s):

Patel ◽

Chugh ◽

Tripathi

Keyword(s):

Prostate Cancer ◽

Advanced Prostate Cancer ◽

Neuroendocrine Differentiation ◽

Prostate Adenocarcinoma ◽

Tumor Evolution ◽

Aggressive Form ◽

Neuroendocrine Prostate Cancer ◽

Key Driver ◽

New Perspective

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 challenge. Even though our knowledge of the mechanisms that mediate neuroendocrine differentiation (NED) is still evolving, the role of androgen deprivation therapy (ADT) as a key driver of this phenomenon is increasingly becoming evident. In this review, we discuss the molecular, cellular, and therapeutic mediators of NED, and emphasize the role of the tumor microenvironment (TME) in orchestrating the phenotype. Understanding the role of the TME in mediating NED could provide us with valuable insights into the plasticity associated with the phenotype, and reveal potential therapeutic targets against this aggressive form of PCa.

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