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 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.

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 Treatment of nonmetastatic castration-resistant prostate cancer: focus on second-generation androgen receptor inhibitors

2021 ◽  
Author(s):  
Fred Saad ◽  
Martin Bögemann ◽  
Kazuhiro Suzuki ◽  
Neal Shore
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Second Generation ◽  
Imaging Techniques ◽  
Specific Antigen ◽  
Conventional Imaging ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Therapeutic Decisions ◽  
Consensus Statements

Abstract Background Nonmetastatic castration-resistant prostate cancer (nmCRPC) is defined as a rising prostate-specific antigen concentration, despite castrate levels of testosterone with ongoing androgen-deprivation therapy or orchiectomy, and no detectable metastases by conventional imaging. Patients with nmCRPC progress to metastatic disease and are at risk of developing cancer-related symptoms and morbidity, eventually dying of their disease. While patients with nmCRPC are generally asymptomatic from their disease, they are often older and have chronic comorbidities that require long-term concomitant medication. Therefore, careful consideration of the benefit–risk profile of potential treatments is required. Methods In this review, we will discuss the rationale for early treatment of patients with nmCRPC to delay metastatic progression and prolong survival, as well as the factors influencing this treatment decision. We will focus on oral pharmacotherapy with the second-generation androgen receptor inhibitors, apalutamide, enzalutamide, and darolutamide, and the importance of balancing the clinical benefit they offer with potential adverse events and the consequential impact on quality of life, physical capacity, and cognitive function. Results and conclusions While the definition of nmCRPC is well established, the advent of next-generation imaging techniques capable of detecting hitherto undetectable oligometastatic disease in patients with nmCRPC has fostered debate on the criteria that inform the management of these patients. However, despite these developments, published consensus statements have maintained that the absence of metastases on conventional imaging suffices to guide such therapeutic decisions. In addition, the prolonged metastasis-free survival and recently reported positive overall survival outcomes of the three second-generation androgen receptor inhibitors have provided further evidence for the early use of these agents in patients with nmCRPC in order to delay metastases and prolong survival. Here, we discuss the benefit–risk profiles of apalutamide, enzalutamide, and darolutamide based on the data available from their pivotal clinical trials in patients with nmCRPC.

scholarly journals Humanization, Radiolabeling and Biodistribution Studies of an IgG1-Type Antibody Targeting Uncomplexed PSA for Theranostic Applications

2021 ◽  
Vol 14 (12) ◽  
pp. 1251
Author(s):  
Joanna Strand ◽  
Kjell Sjöström ◽  
Urpo J. Lamminmaki ◽  
Oskar Vilhelmsson Timmermand ◽  
Sven-Erik Strand ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Binding ◽  
Hek293 Cells ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Biodistribution Studies ◽  
Indium 111 ◽  
Hormone Refractory ◽  
Theranostic Applications

Metastatic castration-resistant prostate cancer is today incurable. Conventional imaging methods have limited detection, affecting their ability to give an accurate outcome prognosis, and current therapies for metastatic prostate cancer are insufficient. This inevitably leads to patients relapsing with castration-resistant prostate cancer. Targeting prostate-specific antigens whose expression is closely linked to the activity in the androgen receptor pathway, and thus the pathogenesis of prostate cancer, is a possible way to increase specificity and reduce off-target effects. We have humanized and evaluated radioimmunoconjugates of a previously murine antibody, m5A10, targeting PSA intended for theranostics of hormone-refractory prostate cancer. The humanized antibody h5A10 was expressed in mammalian HEK293 cells transfected with the nucleotide sequences for the heavy and light chains of the antibody. Cell culture medium was filtered and purified by Protein G chromatography, and the buffer was changed to PBS pH 7.4 by dialysis. Murine and humanized 5A10 were conjugated with p-SCN-Bn-CHX-A”-DTPA. Surface plasmon resonance was used to characterize the binding to PSA of the immunoconjugates. Immunoconjugates were labeled with either indium-111 or lutetium-177. Biodistribution studies of murine and humanized 5A10 were performed in mice with LNCaP xenografts. 5A10 was successfully humanized, and in vivo targeting showed specific binding in xenografts. The results thus give an excellent platform for further theranostic development of humanized 5A10 for clinical applications.

scholarly journals MicroRNA-1205 Regulation of FRYL in Prostate Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Michelle Naidoo ◽  
Fayola Levine ◽  
Tamara Gillot ◽  
Akintunde T. Orunmuyi ◽  
E. Oluwabunmi Olapade-Olaopa ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Neuroendocrine Differentiation ◽  
Castration Resistant Prostate Cancer ◽  
Chromosomal Locus ◽  
Protein Coding ◽  
Castration Resistant ◽  
Dendritic Branching ◽  
Very High

High mortality rates of prostate cancer (PCa) are associated with metastatic castration-resistant prostate cancer (CRPC) due to the maintenance of androgen receptor (AR) signaling despite androgen deprivation therapies (ADTs). The 8q24 chromosomal locus is a region of very high PCa susceptibility that carries genetic variants associated with high risk of PCa incidence. This region also carries frequent amplifications of the PVT1 gene, a non-protein coding gene that encodes a cluster of microRNAs including, microRNA-1205 (miR-1205), which are largely understudied. Herein, we demonstrate that miR-1205 is underexpressed in PCa cells and tissues and suppresses CRPC tumors in vivo. To characterize the molecular pathway, we identified and validated fry-like (FRYL) as a direct molecular target of miR-1205 and observed its overexpression in PCa cells and tissues. FRYL is predicted to regulate dendritic branching, which led to the investigation of FRYL in neuroendocrine PCa (NEPC). Resistance toward ADT leads to the progression of treatment related NEPC often characterized by PCa neuroendocrine differentiation (NED), however, this mechanism is poorly understood. Underexpression of miR-1205 is observed when NED is induced in vitro and inhibition of miR-1205 leads to increased expression of NED markers. However, while FRYL is overexpressed during NED, FRYL knockdown did not reduce NED, therefore revealing that miR-1205 induces NED independently of FRYL.

scholarly journals Anti-Proliferative, Anti-Angiogenic and Safety Profiles of Novel HDAC Inhibitors for the Treatment of Metastatic Castration-Resistant Prostate Cancer

2021 ◽  
Vol 14 (10) ◽  
pp. 1020
Author(s):  
Zohaib Rana ◽  
Sarah Diermeier ◽  
Fearghal P. Walsh ◽  
Muhammad Hanif ◽  
Christian G. Hartinger ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Tube Formation ◽  
In Vivo Studies ◽  
Efficacy And Safety ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Pc3 Cells

Metastatic castration-resistant prostate cancer (CRPC) has a five-year survival rate of 28%. As histone deacetylases (HDACs) are overexpressed in CRPC, the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was trialled in CRPC patients but found to be toxic and inefficacious. Previously, we showed that novel HDAC inhibitors (Jazz90 (N1-hydroxy-N8-(4-(pyridine-2-carbothioamido)phenyl)octanediamide) and Jazz167 ([chlorido(η5-pentamethylcyclopentadieny[1–4](N1-hydroxy-N8-(4-(pyridine-2-carbothioamido-κ2N,S)phenyl)octanediamide)rhodium(III)] chloride) had a higher cancer-to-normal-cell selectivity and superior anti-angiogenic effects in CRPC (PC3) cells than SAHA. Thus, this study aimed to further investigate the efficacy and toxicity of these compounds. HUVEC tube formation assays revealed that Jazz90 and Jazz167 significantly reduced meshes and segment lengths in the range of 55–88 and 43–64%, respectively. However, Jazz90 and Jazz167 did not affect the expression of epithelial-to-mesenchymal transitioning markers E-cadherin and vimentin. Jazz90 and Jazz167 significantly inhibited the growth of PC3 and DU145 spheroids and reduced PC3 spheroid branching. Jazz90 and Jazz167 (25, 50 and 75 mg/kg/day orally for 21 days) were non-toxic in male BALB/c mice. The efficacy and safety of these compounds demonstrate their potential for further in vivo studies in CRPC models.

scholarly journals In vivo quantitative phosphoproteomic profiling identifies novel regulators of castration-resistant prostate cancer growth

Oncogene ◽  
2014 ◽  
Vol 34 (21) ◽  
pp. 2764-2776 ◽  
Author(s):  
N Jiang ◽  
K Hjorth-Jensen ◽  
O Hekmat ◽  
D Iglesias-Gato ◽  
T Kruse ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Growth ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

scholarly journals Crosstalk Between Nuclear MET and SOX9/β-Catenin Correlates with Castration-Resistant Prostate Cancer

2014 ◽  
Vol 28 (10) ◽  
pp. 1629-1639 ◽  
Author(s):  
Yingqiu Xie ◽  
Wenfu Lu ◽  
Shenji Liu ◽  
Qing Yang ◽  
Brett S. Carver ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Combined Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Ablation Therapy ◽  
Androgen Ablation ◽  
Castration Resistant ◽  
Activate Cell ◽  
Androgen Ablation Therapy

Castration-resistant prostate cancer (PCa) (CRPC) is relapse after various forms of androgen ablation therapy and causes a major mortality in PCa patients, yet the mechanism remains poorly understood. Here, we report the nuclear form of mesenchymal epithelial transition factor (nMET) is essential for CRPC. Specifically, nMET is remarkably increased in human CRPC samples compared with naïve samples. Androgen deprivation induces endogenous nMET and promotes cell proliferation and stem-like cell self-renewal in androgen-nonresponsive PCa cells. Mechanistically, nMET activates SRY (sex determining region Y)-box9, β-catenin, and Nanog homeobox and promotes sphere formation in the absence of androgen stimulus. Combined treatment of MET and β-catenin enhances the inhibition of PCa cell growth. Importantly, MET accumulation is detected in nucleus of recurrent prostate tumors of castrated Pten/Trp53 null mice, whereas MET elevation is predominantly found in membrane of naïve tumors. Our findings reveal for the first time an essential role of nMET association with SOX9/β-catenin in CRPC in vitro and in vivo, highlighting that nuclear RTK activate cell reprogramming to drive recurrence, and targeting nMET would be a new avenue to treat recurrent cancers.

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