Alterations in cholesterol regulation contribute to the production of intratumoral androgens during progression to castration-resistant prostate cancer in a mouse xenograft model

The Prostate ◽  
2009 ◽  
Vol 70 (4) ◽  
pp. 390-400 ◽  
Author(s):  
Carlos G. Leon ◽  
Jennifer A. Locke ◽  
Hans H. Adomat ◽  
Susan L. Etinger ◽  
Alexis L. Twiddy ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Xenograft Model ◽  
Castration Resistant Prostate Cancer ◽  
Mouse Xenograft ◽  
Castration Resistant ◽  
Mouse Xenograft Model ◽  
Cholesterol Regulation

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 KLF14 potentiates oxidative adaptation via modulating HO-1 signaling in castrate-resistant prostate cancer

2019 ◽  
Vol 26 (1) ◽  
pp. 181-195 ◽  
Author(s):  
Xiao-hui Luo ◽  
Jian-zhou Liu ◽  
Bo Wang ◽  
Qun-li Men ◽  
Yu-quan Ju ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Xenograft Model ◽  
Specific Inhibitor ◽  
Antioxidant Response ◽  
Heme Oxygenase 1 ◽  
Significant Activity ◽  
Mouse Xenograft ◽  
Castration Resistant ◽  
Mouse Xenograft Model

Insights into the mechanisms by which key factors stimulate cell growth under androgen-depleted conditions is a premise to the development of effective treatments with clinically significant activity in patients with castration-resistant prostate cancer (CRPC). Herein, we report that, the expression of Krüppel-like factor 14 (KLF14), a master transcription factor in the regulation of lipid metabolism, was significantly induced in castration-insensitive PCa cells and tumor tissues from a mouse xenograft model of CRPC. KLF14 upregulation in PCa cells, which was stimulated upstream by oxidative stress, was dependent on multiple pathways including PI3K/AKT, p42/p44 MAPK, AMPK and PKC pathways. By means of ectopic overexpression and genetic inactivation, we further show that KLF14 promoted cell growth via positive regulation of the antioxidant response under androgen-depleted conditions. Mechanistically, KLF14 coupled to p300 and CBP to enhance the transcriptional activation of HMOX1, the gene encoding the antioxidative enzyme heme oxygenase-1 (HO-1) that is one of the most important mechanisms of cell adaptation to stress. Transient knockdown of HMOX1 is sufficient to overcome KLF14 overexpression-potentiated PCa cell growth under androgen-depleted conditions. From a pharmacological standpoint, in vivo administration of ZnPPIX (a specific inhibitor of HO-1) effectively attenuates castration-resistant progression in the mouse xenograft model, without changing KLF14 level. Together, these results provide comprehensive insight into the KLF14-dependent regulation of antioxidant response and subsequent pathogenesis of castration resistance and indicate that interventions targeting the KLF14/HO-1 adaptive mechanism should be further explored for CRPC treatment.

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.

Exisulind (sulindac sulfone) suppresses growth of human prostate cancer in a nude mouse xenograft model by increasing apoptosis

Urology ◽  
1999 ◽  
Vol 53 (2) ◽  
pp. 440-445 ◽  
Author(s):  
Erik T Goluboff ◽  
Ahmad Shabsigh ◽  
James A Saidi ◽  
I.Bernard Weinstein ◽  
Nandita Mitra ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Nude Mouse ◽  
Xenograft Model ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model

scholarly journals TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer

2019 ◽  
Author(s):  
Geun Taek Lee ◽  
Won Tae Kim ◽  
Young Suk Kwon ◽  
Ganesh Palapattu ◽  
Rohit Mehra ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Xenograft Model ◽  
Neuroendocrine Differentiation ◽  
Treatment Resistance ◽  
Parental Cell ◽  
Parental Cell Line ◽  
Castration Resistant Prostate Cancer ◽  
Expression Levels ◽  
Mouse Xenograft Model

AbstractIn treating patients with castration resistant prostate cancer (CRPC), enzalutamide, the second-generation androgen receptor (AR) antagonist, is an accepted standard of care. However, clinical benefits are limited to a median time of 4.8 months because resistance inevitably emerges. To determine the mechanism of treatment resistance, we carried out a RNA sequence analysis and found increased expression levels of neuroendocrine markers in the enzalutamide-resistant LNCaP human prostate cancer (CaP) cell line when compared to the parental cell line. Subsequent studies demonstrated that TCF4, a transcription factor implicated in Wnt signaling, mediated neuroendocrine differentiation (NED) in response to enzalutamide treatment and was elevated in the enzalutamide-resistant LNCaP. In addition, we observed that PTHrP mediated enzalutamide resistance in tissue culture and inducible TCF4 overexpression resulted in enzalutamide-resistance in a mouse xenograft model. Finally, small molecule inhibitors of TCF4 or PTHrP partially reversed enzalutamide resistance in CaP cells. When tissues obtained from men who died of metastatic CaP were examined, a positive correlation was found between the expression levels of TCF4 and PTHrP. Taken together, the current results indicate that TCF4 induces enzalutamide resistance via NED in CaP.

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