scholarly journals 677 IDENTIFICATION OF EP4 AS A POTENTIAL TARGET FOR THE TREATMENT OF CASTRATION-RESISTANT PROSTATE CANCER USING A NOVEL XENOGRAFT MODEL

2010 ◽  
Vol 183 (4S) ◽  
Author(s):  
Naoki Terada ◽  
Yosuke Shimizu ◽  
Tomomi Kamba ◽  
Takahiro Inoue ◽  
Atsushi Maeno ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Xenograft Model ◽  
Castration Resistant Prostate Cancer ◽  
Potential Target ◽  
Castration Resistant

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 Distinct DNA methylation patterns associated with treatment resistance in metastatic castration resistant prostate cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Madonna R. Peter ◽  
Misha Bilenky ◽  
Alastair Davies ◽  
Ruth Isserlin ◽  
Gary D. Bader ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Advanced Disease ◽  
Xenograft Model ◽  
Treatment Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Clinical Progression ◽  
Treatment Target ◽  
Castration Resistant ◽  
Genome Wide ◽  
Methylation Patterns

AbstractAndrogens are a major driver of prostate cancer (PCa) and continue to be a critical treatment target for advanced disease, which includes castration therapy and antiandrogens. However, resistance to these therapies leading to metastatic castration-resistant prostate cancer (mCRPC), and the emergence of treatment-induced neuroendocrine disease (tNEPC) remains an ongoing challenge. Instability of the DNA methylome is well established as a major hallmark of PCa development and progression. Therefore, investigating the dynamics of the methylation changes going from the castration sensitive to the tNEPC state would provide insights into novel mechanisms of resistance. Using an established xenograft model of CRPC, genome-wide methylation analysis was performed on cell lines representing various stages of PCa progression. We confirmed extensive methylation changes with the development of CRPC and tNEPC using this model. This included key genes and pathways associated with cellular differentiation and neurodevelopment. Combined analysis of methylation and gene expression changes further highlighted genes that could potentially serve as therapeutic targets. Furthermore, tNEPC-related methylation signals from this model were detectable in circulating cell free DNA (cfDNA) from mCRPC patients undergoing androgen-targeting therapies and were associated with a faster time to clinical progression. These potential biomarkers could help with identifying patients with aggressive disease.

scholarly journals ISL1 Romotes Enzalutamide Resistance in Castration-resistant Prostate Cancer (CRPC) through Epithelial to Mesenchymal Transition (EMT)

2021 ◽  
Author(s):  
Jae Duck Choi ◽  
Tae Jin Kim ◽  
Byong Chang Jeong ◽  
Hwang Gyun Jeon ◽  
Seong Soo Jeon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Epithelial Mesenchymal Transition ◽  
Mrna Level ◽  
Xenograft Model ◽  
Resistant Cell Line ◽  
Castration Resistant Prostate Cancer ◽  
Mesenchymal Transition ◽  
Knock Down ◽  
Castration Resistant

Abstract Abnormal expression of insulin gene enhancer-binding protein 1 (ISL1) has been demonstrated to be closely associated with cancer development and progression in several cancers. However, little is known about ISL1 expression in metastatic castration-resistant prostate cancer (CRPC). ISL1 has also been recognized as a positive modulator of epithelial-mesenchymal transition (EMT). In this study, we focused on ISL1 which showed maximum upregulation at the mRNA level in the enzalutamide-resistant cell line. Accordingly, we found that ISL1 was overexpressed in enzalutamide-resistant C4-2B cells and its expression was significantly related to EMT. Our findings reveal the important role of ISL1 in androgen receptor (AR)-dependent prostate cancer cell growth; ISL1 knockdown reduced the AR activity and cell growth. ISL1 knockdown using small-interfering RNA inhibited AR, PSA, and EMT-related protein expression in C4-2B ENZR cells. In addition, knock-down ISL1 reduced the levels of AKT and p65 phosphorylation in C4-2B ENZR cells and these suggest that knock-down ISL1 suppresses EMT in part by targeting the AKT/ NF-κB pathway. Further, ISL1 downregulation could effectively inhibit tumor growth in a human CRPC xenograft model. Together, the present study shows that downregulation of ISL1 expression is necessary for overcoming enzalutamide resistance and improving the survival of CRPC patients.

1284 LOW DOSE DOCETAXEL ENHANCES THE SENSITIVITY OF S-1 IN A XENOGRAFT MODEL OF HUMAN CASTRATION RESISTANT PROSTATE CANCER

2011 ◽  
Vol 185 (4S) ◽  
Author(s):  
Masanori Hasegawa ◽  
Akira Miyajima ◽  
Takeo Kosaka ◽  
Yota Yasumizu ◽  
Nobuyuki Tanaka ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Low Dose ◽  
Xenograft Model ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

scholarly journals ISL1 promotes enzalutamide resistance in castration-resistant prostate cancer (CRPC) through epithelial to mesenchymal transition (EMT)

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jae Duck Choi ◽  
Tae Jin Kim ◽  
Byong Chang Jeong ◽  
Hwang Gyun Jeon ◽  
Seong Soo Jeon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Epithelial Mesenchymal Transition ◽  
Mrna Level ◽  
Xenograft Model ◽  
Resistant Cell Line ◽  
Castration Resistant Prostate Cancer ◽  
Mesenchymal Transition ◽  
Knock Down ◽  
Castration Resistant

AbstractAbnormal expression of insulin gene enhancer-binding protein 1 (ISL1) has been demonstrated to be closely associated with cancer development and progression in several cancers. However, little is known about ISL1 expression in metastatic castration-resistant prostate cancer (CRPC). ISL1 has also been recognized as a positive modulator of epithelial–mesenchymal transition (EMT). In this study, we focused on ISL1 which showed maximum upregulation at the mRNA level in the enzalutamide-resistant cell line. Accordingly, we found that ISL1 was overexpressed in enzalutamide-resistant C4-2B cells and its expression was significantly related to EMT. Our findings reveal the important role of ISL1 in androgen receptor (AR)-dependent prostate cancer cell growth; ISL1 knockdown reduced the AR activity and cell growth. ISL1 knockdown using small-interfering RNA inhibited AR, PSA, and EMT-related protein expression in C4-2B ENZR cells. In addition, knock-down ISL1 reduced the levels of AKT and p65 phosphorylation in C4-2B ENZR cells and these suggest that knock-down ISL1 suppresses EMT in part by targeting the AKT/NF-κB pathway. Further, ISL1 downregulation could effectively inhibit tumor growth in a human CRPC xenograft model. Together, the present study shows that downregulation of ISL1 expression is necessary for overcoming enzalutamide resistance and improving the survival of CRPC patients.

Activity of oral VT-464, a selective CYP17-lyase inhibitor, in the LNCaP prostate cancer xenograft.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4671-4671
Author(s):  
William Douglas Figg ◽  
Shawn D. Spencer ◽  
Stephen T Pisle ◽  
Heather M Pressler ◽  
Sarah M Troutman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Growth Inhibition ◽  
Xenograft Model ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Fda Approval ◽  
Dependent Growth ◽  
To Receive ◽  
Dose Dependent

4671 Background: With the FDA approval of abiraterone acetate, inhibition of CYP17 (17α hydroxylase/C17, 20-lyase) is now a validated approach to the treatment of castration-resistant prostate cancer. VT-464 is a novel, selective CYP17-lyase inhibitor with decreased activity against CYP17 hydroxylase (less mineralcocorticoid and glucocorticoid effects). The study objectives were to observe the effects of VT-464 in a prostate cancer xenograft model and to compare its activity to abiraterone acetate and surgical castration. Methods: SCID mice were implanted subcutaneously with LNCaP cells. When tumors reached 100 mm3, mice were randomized to receive vehicle (0.5% CMC in saline, 5 mL/kg), VT-464 at 15, 50, or 100 mg/kg p.o. b.i.d. A second cohort of LNCaP tumor-bearing mice received vehicle, surgical castration, or VT-464, or abiraterone acetate at 100 mg/kg p.o. b.i.d. for 28 days. Terminal blood and tumor concentrations were analyzed on day 28, four hours after the last dose. Results: In the first LNCaP xenograft cohort, percent growth inhibition (± S.E.) of 9.6 (±15.6), 38.5 (±12.4), and 73.9 (±13.2) was observed on day 21 of treatment for VT-464 doses of 15, 50, and 100 mg/kg, respectively. Growth reduction at 100 mg/kg was statistically significant compared to vehicle control from day 7 to 28. VT-464 was well tolerated with insignificant weight loss at all doses. In the second cohort, VT-464-treated (100 mg/kg) mice had significantly reduced tumor volumes on day 28 compared to control and abiraterone acetate (p<0.05, p<0.01, respectively). Reduction in tumor volumes were similar between VT-464-treated (100 mg/kg) and castrate animals. Plasma and tumor analyses revealed much greater plasma and tumor exposure of VT-464 compared to abiraterone acetate. Conclusions: VT-464 exhibited dose-dependent growth inhibition with significantly reduced tumor volumes at the highest dose compared to abiraterone acetate. The activity in VT-464-treated animals was similar to that of castrate animals. These preclinical results show promising activity of VT-464 in the treatment of prostate cancer.

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