scholarly journals Extracellular Microenvironment in Patient-derived Hydrogel Organoids of Prostate Cancer Regulates Therapeutic Response

2020 ◽  
Author(s):  
Matthew J Mosquera ◽  
Rohan Bareja ◽  
Jacob M Bernheim ◽  
Muhammad Asad ◽  
Cynthia Cheung ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Inflammatory Cells ◽  
Cellular Reprogramming ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Prostate Cells ◽  
Synthetic Hydrogel ◽  
Neuroendocrine Prostate Cancer ◽  
Prostate Cancers ◽  
Novel Target

Following treatment with androgen receptor (AR) pathway inhibitors, ~20% of prostate cancer patients progress by shedding their dependence on AR. These tumors undergo epigenetic reprogramming turning castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) into neuroendocrine prostate cancer (CRPC-NEPC). Currently, no targeted therapies are available for CRPC-NEPCs. A major hurdle in the development of new therapies and treatment of CRPC-NEPC is the lack of accurate models to test candidate treatments. Such models would ideally capture components of the tumor microenvironment (TME) factors, which likely regulate the phenotypic, genetic, and epigenetic underpinnings of this aggressive subset. The TME is a complex system comprised not only of malignant prostate cells but also stromal and inflammatory cells and a scaffold of extracellular matrix (ECM). ECM proteins are implicated in the survival and progression of cancer and development of chemoresistance, while are equally integral to the development of prostate cancer organoids. Here, using a combination of patient tumor proteomics and RNA sequencing, we define putative ECM cues that may guide the growth of prostate tumors in patients. Using this molecular information, we developed synthetic hydrogels that recapitulate the tumor ECM. Organoids cultured in the synthetic hydrogel niches demonstrate that ECM subtypes regulate the morphology, transcriptome, and epigenetics hallmarks of CRPC-Adeno and CRPC-NEPC. CRPC-NEPC organoid showed a differential response to small molecule inhibitors of epigenetic repressor EZH2 and Dopamine Receptor D2 (DRD2), the latter being a novel target in CRPC-NEPC when grown in tumor-specific ECM. Finally, in those synthetic ECM niches where drug resistance was observed in CRPC-NEPCs, cellular reprogramming by a synergistic combination of EZH2 inhibitors with DRD2 antagonists inhibited tumor growth. The synthetic platform can provide a more realistic prostate-specific microenvironment and subsequently enable the development of effective targeted therapeutics for prostate cancers.

scholarly journals Novel, non-invasive markers for detecting therapy induced neuroendocrine differentiation in castration-resistant prostate cancer patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Divya Bhagirath ◽  
Michael Liston ◽  
Theresa Akoto ◽  
Byron Lui ◽  
Barbara A. Bensing ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Neuroendocrine Differentiation ◽  
Extracellular Vesicle ◽  
Machine Learning Algorithms ◽  
Castration Resistant Prostate Cancer ◽  
Cellular Models ◽  
Non Invasive ◽  
Castration Resistant ◽  
Neuroendocrine Prostate Cancer

AbstractNeuroendocrine prostate cancer (NEPC), a highly aggressive variant of castration-resistant prostate cancer (CRPC), often emerges upon treatment with androgen pathway inhibitors, via neuroendocrine differentiation. Currently, NEPC diagnosis is challenging as available markers are not sufficiently specific. Our objective was to identify novel, extracellular vesicles (EV)-based biomarkers for diagnosing NEPC. Towards this, we performed small RNA next generation sequencing in serum EVs isolated from a cohort of CRPC patients with adenocarcinoma characteristics (CRPC-Adeno) vs CRPC-NE and identified significant dysregulation of 182 known and 4 novel miRNAs. We employed machine learning algorithms to develop an ‘EV-miRNA classifier’ that could robustly stratify ‘CRPC-NE’ from ‘CRPC-Adeno’. Examination of protein repertoire of exosomes from NEPC cellular models by mass spectrometry identified thrombospondin 1 (TSP1) as a specific biomarker. In view of our results, we propose that a miRNA panel and TSP1 can be used as novel, non-invasive tools to identify NEPC and guide treatment decisions. In conclusion, our study identifies for the first time, novel non-invasive exosomal/extracellular vesicle based biomarkers for detecting neuroendocrine differentiation in advanced castration resistant prostate cancer patients with important translational implications in clinical management of these patients that is currently extremely challenging.

Sex Hormones and Prostate Cancer

2020 ◽  
Vol 71 (1) ◽  
pp. 33-45 ◽  
Author(s):  
Richard J. Auchus ◽  
Nima Sharifi
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Current Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
History Of ◽  
Prostate Cancer Research ◽  
Prostate Cancers ◽  
Androgen Independent ◽  
Transition Studies

The prostate is an androgen-dependent organ that develops only in male mammals. Prostate cancer is the most common nonskin malignancy in men and the second leading cause of cancer deaths. Metastatic prostate cancer initially retains its androgen dependence, and androgen-deprivation therapy often leads to disease control; however, the cancer inevitably progresses despite treatment as castration-resistant prostate cancer, the lethal form of the disease. Although it was assumed that the cancer became androgen independent during this transition, studies over the last two decades have shown that these tumors evade treatment via mechanisms that augment acquisition of androgens from circulating precursors, increase sensitivity to androgens and androgen precursors, bypass the androgen receptor, or a combination of these mechanisms. This review summarizes the history of prostate cancer research leading to the contemporary view of androgen dependence for prostate cancers and the current treatment approaches based on this modern paradigm.

scholarly journals Identification of Novel Diagnosis Biomarkers for Therapy-Related Neuroendocrine Prostate Cancer

2021 ◽  
Vol 27 ◽  
Author(s):  
Cuijian Zhang ◽  
Jinqin Qian ◽  
Yucai Wu ◽  
Zhenpeng Zhu ◽  
Wei Yu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Characteristics ◽  
Expression Profiles ◽  
Prostate Adenocarcinoma ◽  
Diagnostic Tools ◽  
Receptor Interaction ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Neuroendocrine Prostate Cancer ◽  
Platinum Based Chemotherapy

Background: Therapy-related neuroendocrine prostate cancer (NEPC) is a lethal castration-resistant prostate cancer (CRPC) subtype that, at present, lacks well-characterized molecular biomarkers. The clinical diagnosis of this disease is dependent on biopsy and histological assessment: methods that are experience-based and easily misdiagnosed due to tumor heterogeneity. The development of robust diagnostic tools for NEPC may assist clinicians in making medical decisions on the choice of continuing anti-androgen receptor therapy or switching to platinum-based chemotherapy.Methods: Gene expression profiles and clinical characteristics data of 208 samples of metastatic CRPC, including castration-resistant prostate adenocarcinoma (CRPC-adeno) and castration-resistant neuroendocrine prostate adenocarcinoma (CRPC-NE), were obtained from the prad_su2c_2019 dataset. Weighted Gene Co-expression Network Analysis (WGCNA) was subsequently used to construct a free-scale gene co-expression network to study the interrelationship between the potential modules and clinical features of metastatic prostate adenocarcinoma and to identify hub genes in the modules. Furthermore, the least absolute shrinkage and selection operator (LASSO) regression analysis was used to build a model to predict the clinical characteristics of CRPC-NE. The findings were then verified in the nepc_wcm_2016 dataset.Results: A total of 51 co-expression modules were successfully constructed using WGCNA, of which three co-expression modules were found to be significantly associated with the neuroendocrine features and the NEPC score. In total, four novel genes, including NPTX1, PCSK1, ASXL3, and TRIM9, were all significantly upregulated in NEPC compared with the adenocarcinoma samples, and these genes were all associated with the neuroactive ligand receptor interaction pathway. Next, the expression levels of these four genes were used to construct an NEPC diagnosis model, which was successfully able to distinguish CRPC-NE from CRPC-adeno samples in both the training and the validation cohorts. Moreover, the values of the area under the receiver operating characteristic (AUC) were 0.995 and 0.833 for the training and validation cohorts, respectively.Conclusion: The present study identified four specific novel biomarkers for therapy-related NEPC, and these biomarkers may serve as an effective tool for the diagnosis of NEPC, thereby meriting further study.

Novel biomarker of specific castration-resistant prostate cancer (CRPC) by exploring the proteome analysis.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 247-247 ◽  
Author(s):  
Hiroji Uemura ◽  
Noriaki Arakawa ◽  
Yusuke Itoh ◽  
Takashi Kawahara ◽  
Yasuhide Miyoshi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Proteome Analysis ◽  
Human Prostate ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Prostate Hyperplasia ◽  
Castration Resistant ◽  
Significant Difference ◽  
Prostate Cancers

247 Background: It is well known that prostate specific antigen (PSA) level has no reliable correlation with pathological malignancy of prostate cancer and is not a predictor for the development of castration resistant prostate cancer (CRPC). The aim of this study is to explore novel biomarkers to predict the development of CRPC by using proteomics from secreted proteins from human prostate cancer cells. Methods: The proteins secreted from 6 prostate cancers in culture medium were analyzed and compared with 8 other cancer cells including renal and urothelial cancers using LTQ Orbitrap mass spectrometer. With the focus on high tissue specificity, the candidate biomarker proteins were then identified through analysis of gene expressions in proteins common to human prostate cancers by real time qPCR. Next, a system to measure the identified mouse monoclonal antibodies against the focused proteins was established. Finally, serum levels of these proteins from 33 patients with benign prostate hyperplasia (BPH), 31 with untreated prostate cancer (PCa) and 35 with CRPC, were measured. Results: The proteome analysis identified 12 candidates of secreted cell membrane proteins as new biomarkers. The proteome analysis indicated that not only matured GDF15, but pro-peptide as well as fragments (GDDP) are released from prostate cancer cells. Patients’ serum was analyzed for matured and pro-peptide GDF15 using ELISA and immunoprecipitation-MRM mass spectrometry. The results showed that the serum level of GDDP-1, one of the processing forms of GDDP, was significantly higher in CRPC than those in BPH and untreated PCa (P < 0.01). ROC analysis also showed that the AUC of GDDP-1(0.86) was higher than that of matured GDF15 (0.76). When the cutoff value of GDDP-1 was set at 4.0 ng/mL, there was a significant difference of overall survival (OS) in CRPC patients between those with more than 4.0 ng/mL compared to less than 4.0 ng/mL of GDDP-1, whereas there was no significant difference of OS measurable by PSA in CRPC patients. These data suggest that GDDP-1 may be a novel biomarker for CRPC. Conclusions: GDDP-1 shows potential as a novel biomarker for CRPC.

scholarly journals Immunotherapy and Immunotherapy Combinations in Metastatic Castration-Resistant Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 334
Author(s):  
Dhruv Bansal ◽  
Melissa A. Reimers ◽  
Eric M. Knoche ◽  
Russell K. Pachynski
Keyword(s):  
Prostate Cancer ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Specific Antigen ◽  
Parp Inhibitors ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Immunosuppressive Tumor Microenvironment ◽  
Prostate Cancers ◽  
Past Experiences

Although most prostate cancers are localized, and the majority are curable, recurrences occur in approximately 35% of men. Among patients with prostate-specific antigen (PSA) recurrence and PSA doubling time (PSADT) less than 15 months after radical prostatectomy, prostate cancer accounted for approximately 90% of the deaths by 15 years after recurrence. An immunosuppressive tumor microenvironment (TME) and impaired cellular immunity are likely largely responsible for the limited utility of checkpoint inhibitors (CPIs) in advanced prostate cancer compared with other tumor types. Thus, for immunologically “cold” malignancies such as prostate cancer, clinical trial development has pivoted towards novel approaches to enhance immune responses. Numerous clinical trials are currently evaluating combination immunomodulatory strategies incorporating vaccine-based therapies, checkpoint inhibitors, and chimeric antigen receptor (CAR) T cells. Other trials evaluate the efficacy and safety of these immunomodulatory agents’ combinations with standard approaches such as androgen deprivation therapy (ADT), taxane-based chemotherapy, radiotherapy, and targeted therapies such as tyrosine kinase inhibitors (TKI) and poly ADP ribose polymerase (PARP) inhibitors. Here, we will review promising immunotherapies in development and ongoing trials for metastatic castration-resistant prostate cancer (mCRPC). These novel trials will build on past experiences and promise to usher a new era to treat patients with mCRPC.

scholarly journals Androgen receptor variant shows heterogeneous expression in prostate cancer according to differentiation stage

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Ada Gjyrezi ◽  
Giuseppe Galletti ◽  
Jiaren Zhang ◽  
Daniel Worroll ◽  
Michael Sigouros ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Castration Resistant Prostate Cancer ◽  
Expression Platform ◽  
Castration Resistant ◽  
Neuroendocrine Prostate Cancer ◽  
Gene Expression Platform ◽  
Heterogeneous Expression ◽  
Droplet Pcr ◽  
Differentiation Stage

AbstractQuantitation of androgen receptor variant (AR-V) expression in circulating tumor cells (CTCs) from patients with metastatic castration-resistant prostate cancer (mCRPC) has great potential for treatment customization. However, the absence of a uniform CTC isolation platform and consensus on an analytical assay has prevented the incorporation of these measurements in routine clinical practice. Here, we present a single-CTC sensitive digital droplet PCR (ddPCR) assay for the quantitation of the two most common AR-Vs, AR-V7, and AR-v567es, using antigen agnostic CTC enrichment. In a cohort of 29 mCRPC patients, we identify AR-V7 in 66% and AR-v567es in 52% of patients. These results are corroborated using another gene expression platform (NanoStringTM) and by analysis of RNA-Seq data from patients with mCRPC (SU2C- PCF Dream Team). We next quantify AR-V expression in matching EpCAM-positive vs EpCAM-negative CTCs, as EpCAM-based CTC enrichment is commonly used. We identify lower AR-V prevalence in the EpCAM-positive fraction, suggesting that EpCAM-based CTC enrichment likely underestimates AR-V prevalence. Lastly, using single CTC analysis we identify enrichment for AR-v567es in patients with neuroendocrine prostate cancer (NEPC) indicating that AR-v567es may be involved in lineage plasticity, which warrants further mechanistic interrogation.

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