scholarly journals PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer

2016 ◽  
Vol 113 (26) ◽  
pp. 7124-7129 ◽  
Author(s):  
Kanak Raina ◽  
Jing Lu ◽  
Yimin Qian ◽  
Martha Altieri ◽  
Deborah Gordon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Small Molecule ◽  
Xenograft Model ◽  
The United States ◽  
Castration Resistant Prostate Cancer ◽  
Secondary Resistance ◽  
Cellular Models ◽  
Castration Resistant ◽  
Mouse Xenograft Model ◽  
Bet Inhibitors

Prostate cancer has the second highest incidence among cancers in men worldwide and is the second leading cause of cancer deaths of men in the United States. Although androgen deprivation can initially lead to remission, the disease often progresses to castration-resistant prostate cancer (CRPC), which is still reliant on androgen receptor (AR) signaling and is associated with a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance invariably emerges, and new therapies are urgently needed. Recently, inhibitors of bromodomain and extra-terminal (BET) family proteins have shown growth-inhibitory activity in preclinical models of CRPC. Here, we demonstrate that ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. Unlike BET inhibitors, ARV-771 results in suppression of both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model. This study is, to our knowledge, the first to demonstrate efficacy with a small-molecule BET degrader in a solid-tumor malignancy and potentially represents an important therapeutic advance in the treatment of CRPC.

Effect of the novel anti-androgen ARN-509 on response and seizure in castration-resistant prostate cancer models.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 28-28
Author(s):  
J. H. Hager ◽  
N. D. Smith ◽  
E. Bischoff ◽  
M. E. Jung ◽  
C. L. Sawyers ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Second Generation ◽  
Xenograft Model ◽  
Seizure Threshold ◽  
High Dose ◽  
Castration Resistant Prostate Cancer ◽  
Durable Response ◽  
Castration Resistant ◽  
Mouse Xenograft Model

28 Background: ARN-509 is a second-generation anti-androgen discovered in a screen to identify full androgen receptor (AR) antagonists in the context of AR over-expressing prostate cancer cells, a model for castration resistant prostate cancer (CRPC). It has been reported that other second-generation anti-androgens, MDV3100 and BMS-641988, can induce seizures at high dose in pre-clinical species and man and that this is mediated through antagonism of the CNS-based GABAA receptor. To define the clinical potential of ARN-509, we carried out a comprehensive assessment of its in vitro and in vivo activity in validated models of CRPC and assessed its seizure inducing potential. Methods: ARN-509 and MDV3100 were profiled in a series of assays to monitor both on- and off-target activity. Comparative in vivo efficacy in the LNCaP/AR mouse xenograft model of CRPC and pharmacokinetics were determined. Seizure inducing potential was assessed in an acute pentylenetetrazol (PTZ) infusion model. Results: In vivo, in the LNCaP/AR model of CRPC, an ARN-509 dose of 10 mg/kg/day exhibited tumors regressions equivalent in frequency and magnitude to a 30 mg/kg/day dose of MDV3100. Tumor re-growth following once daily dosing (30 mg/kg) for 28 days revealed that ARN-509 treated tumors exhibited a more durable response than MDV3100 treated tumors as evidenced by a significantly longer time to re-growth. At doses that yielded equivalent degree of tumor regression, the steady state plasma and brain levels were significantly lower for ARN-509 (10 mg/kg) than MDV3100 (30 mg/kg). ARN-509 and MDV3100 exhibit similar binding affinity to the GABAA receptor; IC50 3.0 and 2.7 mM, respectively. In vivo seizure potential of ARN-509 and MDV3100 was assessed in an acute PTZ infusion model in mice. MDV3100 was found to produce a dose dependant lowering of seizure threshold, while ARN-509 had no effect at any dose tested. Conclusions: ARN-509 is a second-generation anti-androgen with significant efficacy and an appropriate safety profile that supports its clinical development in both CRPC and earlier stages of prostate cancer. ARN-509 is currently in a phase I/II study in CRPC patients. [Table: see text]

scholarly journals Cancer-driven IgG promotes the development of castration-resistant Prostate Cancer though the SOX2-CIgG pathway

2020 ◽  
Author(s):  
Caipeng Qin ◽  
Zhengzuo Sheng ◽  
Xinmei Huang ◽  
Jingshu Tang ◽  
Yang Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Androgen Deprivation Therapy ◽  
Xenograft Model ◽  
Androgen Deprivation ◽  
Cancer Tissue ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cell ◽  
Castration Resistant ◽  
Mouse Xenograft Model

Abstract Background: Although Androgen deprivation therapy (ADT) is the initial treatment strategy for prostate cancer, recurrent castration-resistant prostate cancer (CRPC) eventually ensues. In this study, cancer-derived immunoglobulin G(CIgG) was found to be induced after ADT, identifying CIgG as a potential CRPC driver gene.Methods: The expression of CIgG and its clinical significance in prostate cancer tissue was analyzed by TCGA database and immunohistochemistry. Subsequently, the sequence features of prostate cell line (LNcap, DU145, PC3) VHDJH rearrangements were analyzed via comparison with the best matching functional germline IgVH, IgDH and IgJH genes. We also assessed the effect of CIgG on the migratory, invasive and proliferative abilities of prostate cancer cells in vitro and vivo. Cells with high CIgG expression (CIgGhigh) and low CIgG expression (CIgG-/low) from the PC3 cell line were sorted by FACS using a CIgG monoclonal antibody named RP215, then, suspended microsphere, colony formation and drug-resistant assays were performed. A NOD/SCID mouse tumor xenograft model was developed for the study of the tumorigenic effects of the different cell populations. The AR-SOX2-CIgG signaling pathway was validated by immunohistochemistry, immunofluorescence, qRT-PCR, Western blot, luciferase and ChIP assays and bioinformatics analyses. Finally, we investigated the effect of RP215 inhibition on the progression of prostate cancer in vivo using a Babl/c nude mouse xenograft model.Results: We demonstrated that CIgG was induced by androgen deprivation therapy (ADT) and upregulated by SOX2 [SRY (sex determining region Y)-box 2] in prostate cancer, which may promote the development of CRPC. In addition, our findings underscore a novel role of CIgG signaling in the maintenance of stemness and the progression of cancer through MARK/ERK and AKT in prostate cancer.Conclusion: Our data suggests that CIgG could be a driver of CRPC development, and that targeting the SOX2-CIgG axis may therefore inhibit CRPC development after ADT.

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.

Metastatic Castration-Resistant Prostate Cancer: Academic Insights and Perspectives Analysis

2019 ◽  
Author(s):  
Lugeng He ◽  
Hui Fang ◽  
Chao Chen ◽  
Yanqi Wu ◽  
Yuyong Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Developed Countries ◽  
The United States ◽  
Vital Role ◽  
Cancer Center ◽  
Castration Resistant Prostate Cancer ◽  
Research Areas ◽  
Castration Resistant ◽  
The Usa ◽  
Future Direction

Abstract Background In recent years, metastatic castration-resistant prostate cancer (MCRPC) and studies related to MCRPC have drawn global attention. The main objective of this bibliometric study was to provide an overview of MCRPC, explore clusters and trends in research and investigate the future direction of MCRPC research. Methods A total of 4,089 publications published between 1979 and 2018 were retrieved from the Web of Science (WoS) Core Collection database. Different aspects of MCRPC research, including the countries/territories, institutions, journals, authors, research areas, funding agencies and author keywords, were analyzed. Results The number of annual MCRPC publications increased rapidly after 2010. American researchers played a vital role in this increase, as they published the most publications. The most productive institution was Memorial Sloan Kettering Cancer Center. De Bono, JS (the United Kingdom [UK]) and Scher, HI (the United States of America [USA]) were the two most productive authors. The National Institutes of Health (NIH) funded the largest number of published papers. Analyses of keywords suggested that therapies (abiraterone, enzalutamide, etc.) would attracted global attention after US Food and Drug Administration (FDA) approval. Conclusions Developed countries, especially the USA,were the leading nations for MCRPC research because of their abundant funding and frequent international collaborations. Therapy was one of the most vital aspects of MCRPC research. Therapies targeting DNA repair or the androgen receptor (AR) signing pathway and new therapies especially prostate-specific membrane antigen (PSMA)-based radioligand therapy (RLT) would be the next focus of MCRPC research.

scholarly journals Treatment characteristics for nonmetastatic castration-resistant prostate cancer in the United States, Europe and Japan

2019 ◽  
Vol 15 (35) ◽  
pp. 4069-4081 ◽  
Author(s):  
Ruchitbhai Shah ◽  
Marc Botteman ◽  
Reginald Waldeck
Keyword(s):  
Prostate Cancer ◽  
Eastern Cooperative Oncology Group ◽  
Patient Characteristics ◽  
The United States ◽  
Treatment Patterns ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Synthesis ◽  
Castration Resistant ◽  
The Us ◽  
Androgen Synthesis Inhibitors

Aim: We conducted this study to describe nonmetastatic castration-resistant prostate cancer (nmCRPC) patient characteristics and treatment patterns in the US, Europe and Japan. Materials & methods: Descriptive analyses were conducted using the 2015–2017 Ipsos Global Oncology Monitor Database. Results: A total of 2065 (442 in the US, 509 in Europe and 1114 in Japan) patients (median age: 74–80 years; stage III at diagnosis : 38.5%; Eastern Cooperative Oncology Group [ECOG] score ≤1: 79.4%; treated by urologist : 88.4%) were included in the analytic cohort. Luteinizing hormone-releasing hormone agonists and antiandrogens were the most commonly used first regimen treatments. With subsequent nmCRPC regimens their use decreased, while the use of chemotherapy, corticosteroids, androgen synthesis inhibitors and second-generation androgen receptor inhibitors increased. Conclusion: These data represent real-world treatment patterns in nmCRPC.

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