scholarly journals ARVib suppresses growth of advanced prostate cancer via inhibition of androgen receptor signaling

Oncogene ◽  
2021 ◽  
Author(s):  
Chengfei Liu ◽  
Cameron M. Armstrong ◽  
Shu Ning ◽  
Joy C. Yang ◽  
Wei Lou ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Progression ◽  
Nuclear Translocation ◽  
Treatment Resistance ◽  
Hsp70 Expression ◽  
Castration Resistant Prostate Cancer ◽  
Downstream Target

AbstractTargeting androgen signaling with the second-generation anti-androgen drugs, such as enzalutamide (Enza), abiraterone (Abi), apalutamide (Apal), and darolutamide (Daro), is the mainstay for the treatment of castration-resistant prostate cancer (CRPC). While these treatments are effective initially, resistance occurs frequently. Continued expression of androgen receptor (AR) and its variants such as AR-V7 despite AR-targeted therapy contributes to treatment resistance and cancer progression in advanced CRPC patients. This highlights the need for new strategies blocking continued AR signaling. Here, we identify a novel AR/AR-V7 degrader (ARVib) and found that ARVib effectively degrades AR/AR-V7 protein and attenuates AR/AR-V7 downstream target gene expression in prostate cancer cells. Mechanistically, ARVib degrades AR/AR-V7 protein through the ubiquitin-proteasome pathway mediated by HSP70/STUB1 machinery modulation. ARVib suppresses HSP70 expression and promotes STUB1 nuclear translocation, where STUB1 binds to AR/AR-V7 and promotes its ubiquitination and degradation. ARVib significantly inhibits resistant prostate tumor growth and improves enzalutamide treatment in vitro and in vivo. These data suggest that ARVib has potential for development as an AR/AR-V7 degrader to treat resistant CRPC.

scholarly journals Huaier Extract Inhibits Prostate Cancer Growth via Targeting AR/AR-V7 Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhengfang Liu ◽  
Cheng Liu ◽  
Keqiang Yan ◽  
Jikai Liu ◽  
Zhiqing Fang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Nuclear Translocation ◽  
Mrna Levels ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Specific Protease ◽  
Hormone Sensitive

The androgen receptor (AR) plays a pivotal role in prostatic carcinogenesis, and it also affects the transition from hormone sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC). Particularly, the persistent activation of the androgen receptor and the appearance of androgen receptor splicing variant 7 (AR-V7), could partly explain the failure of androgen deprivation therapy (ADT). In the present study, we reported that huaier extract, derived from officinal fungi, has potent antiproliferative effects in both HSPC and CRPC cells. Mechanistically, huaier extract downregulated both full length AR (AR-FL) and AR-V7 mRNA levels via targeting the SET and MYND domain-containing protein 3 (SMYD3) signaling pathway. Huaier extract also enhanced proteasome-mediated protein degradation of AR-FL and AR-V7 by downregulating proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). Furthermore, huaier extract inhibited AR-FL/AR-V7 transcriptional activity and their nuclear translocation. More importantly, our data demonstrated that huaier extract could re-sensitize enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vitro and in vivo models. Our work revealed that huaier extract could be effective for treatment of prostate cancer either as monotherapy or in combination with enzalutamide.

ODM-204: A novel dual inhibitor of CYP17A1 and androgen receptor for the treatment of castration-resistant prostate cancer—Preclinical data.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 221-221
Author(s):  
Riikka Oksala ◽  
Anu Moilanen ◽  
Reetta Riikonen ◽  
Petteri Rummakko ◽  
Riikka Huhtaniemi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Nuclear Translocation ◽  
Leuprolide Acetate ◽  
Male Rats ◽  
Castration Resistant Prostate Cancer ◽  
Dual Inhibitor ◽  
Castration Resistant

221 Background: Castration-resistant prostate cancer (CRPC) is characterized by high androgen receptor (AR) expression and persistent activation of AR signaling axis by residual tissue/tumor androgens. Targeting AR and androgen biosynthesis together may be more effective than either alone. ODM-204 is a novel, non-steroidal dual inhibitor of CYP17A1 and AR, which has shown promising results in preclinical studies. Methods: The binding affinity of ODM-204 to wild type AR was determined in rat prostate cytosolic lysates. The potency and functional activity of ODM-204 to human AR were demonstrated in cells stably transfected with the full-length AR and androgen-responsive reporter gene constructs. In addition, assays for AR nuclear translocation and the transactivation of human AR mutants T877A, W741L, and F876L were conducted. The effects of ODM-204 on the growth of androgen-dependent VCaP and LNCaP cells in vitro and subcutaneously grafted VCaP cells in vivo with the oral dose of 50 mg/kg/day were studied. The inhibition of CYP17A1 by ODM-204 was studied in vitro by using human and rat testicular microsomes and a human adrenal cortex cell line, and in vivo in male rats coadministered with luteinizing hormone releasing hormone agonist leuprolide acetate to mimic clinical situation. Results: ODM-204 is a potent inhibitor of both AR and CYP17A1. It binds to AR with a high affinity (Ki=47 nM) and selectivity and has a high potency towards CYP17A1 (IC50=22 nM). In addition, ODM-204 inhibited testosterone-mediated nuclear translocation of AR and the mutant ARs (IC50 values for AR(T877A), AR(W741L), and AR(F876L) were 95, 277, and 6 nM, respectively), and suppressed androgen-induced cell proliferation of LNCaP (IC50=170 nM) and VCaP (IC50=280 nM) cells. In a VCaP xenograft model, ODM-204 showed significant antitumor activity (tumor growth inhibition=66%). In rats, inhibitory effects of leuprolide acetate on testosterone production and androgen-sensitive organ weights were potentiated by ODM-204. Conclusions: ODM-204 is a promising new dual CYP17A1 and AR inhibitor for the treatment of CRPC. Clinical trials in patients with mCRPC will be started in early 2015.

scholarly journals Macrophage-derived cholesterol contributes to therapeutic resistance in prostate cancer

2021 ◽  
Author(s):  
Asmaa El-Kenawi ◽  
William Dominguez-Viqueira ◽  
Min Liu ◽  
Shivanshu Awasthi ◽  
Aysenur Keske ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Nuclear Translocation ◽  
Cholesterol Metabolism ◽  
Therapeutic Potential ◽  
Cholesterol Homeostasis ◽  
Castration Resistant Prostate Cancer ◽  
Macrophage Depletion

Tumor-associated macrophages are key immune cells associated with cancer progression. Here we sought to determine the role of macrophages in castration-resistant prostate cancer (CRPC) using a syngeneic model that reflected the mutational landscape of the disease. A transcriptomic analysis of CRPC tumors following macrophage depletion revealed lower molecular signatures for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism. Since cholesterol is the precursor of the five major classes of steroid hormones, we reasoned that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Indeed, macrophage depletion reduced the levels of androgens within prostate tumors and restricted androgen receptor (AR) nuclear localization in vitro and in vivo. Macrophages were cholesterol rich and had the ability to transfer cholesterol to tumor cells in vitro, and AR nuclear translocation was inhibited by activation of Liver X Receptor (LXR)-β, the master regulator of cholesterol homeostasis. Finally, combining macrophage depletion with androgen deprivation therapy increased survival, supporting the therapeutic potential of targeting macrophages in CRPC.

A randomized phase II study of OGX-427 plus prednisone (P) versus P alone in patients (pts) with metastatic castration resistant prostate cancer (CRPC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4514-4514 ◽  
Author(s):  
Kim N. Chi ◽  
Sebastien J. Hotte ◽  
Susan Ellard ◽  
Joel Roger Gingerich ◽  
Anthony Michael Joshua ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Single Agent ◽  
Castration Resistant Prostate Cancer ◽  
Disease Response ◽  
Measurable Disease ◽  
The Difference ◽  
Ecog Ps

4514 Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone protein that regulates cell signaling and survival pathways implicated in cancer progression. In prostate cancer models, Hsp27 complexes with androgen receptor (AR) and enhances transactivation of AR-regulated genes. OGX-427 is a 2nd generation antisense oligonucleotide that inhibits Hsp27 expression with in vitro and in vivo efficacy and was well tolerated with single agent activity in phase I studies. Methods: Chemotherapy-naïve pts with no/minimal symptoms were randomized to receive OGX-427 600 mg IV x 3 loading doses then 1000 mg IV weekly with P 5 mg PO BID or P only. Primary endpoint was the proportion of pts progression free (PPF) at 12 weeks (PCWG2 criteria). A 2-stage MinMax design (H0 = 5%, HA >20%, α=0.1, β=0.1) with 32 pts/arm provides 70% power to detect the difference at 0.10 1-sided significance. Secondary endpoints include PSA decline, measurable disease response, and circulating tumour cell (CTC) enumeration. Results: 38 pts have been enrolled; 1st stage of accrual completed with 2nd stage accruing. In the 1st 32 pts randomized (17 to OGX-427+P, 15 to P), baseline median age was 71 years (53-89), ECOG PS 0 or 1 in 66% and 34% of pts, median PSA 66 (6-606), metastases in bone/lymph nodes/liver or lung was 75/56/9%, 31% had prior P treatment, and 93% had ≥5 CTC/7.5 ml. Predominantly grade 1/2 infusion reactions (chills, diarrhea, flushing, nausea, vomiting) occurred in 47% of pts receiving OGX-427+P. One pt on OGX-427+P developed hemolytic uremic syndrome. A PSA decline of ≥50% occurred in 41% of pts on OGX-427+P, and 20% of pts treated with P. A measurable disease partial response was seen in 3/8 (38%) evaluable pts on OGX-427+P and 0/9 pts on P. CTC conversion from ≥5 to <5/7.5 ml occurred in 50% of pts on OGX-427+P and 31% treated with P. Thus far, in 26 evaluable pts the PPF at 12 weeks was 71% (95% CI: 42-92) in OGX-427+P treated pts and 33% (95% CI: 10-65) in pts on P. Conclusions: These data provide clinical evidence for the role of Hsp27 as a therapeutic target in prostate cancer and support continued evaluation of OGX-427 for pts with CRPC. Funded by a grant from the Terry Fox Research Institute.

An oral androgen receptor PROTAC degrader for prostate cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 381-381 ◽  
Author(s):  
Taavi Neklesa ◽  
Lawrence B Snyder ◽  
Ryan R Willard ◽  
Nicholas Vitale ◽  
Kanak Raina ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Drug Exposure ◽  
Point Mutations ◽  
Genetic Alterations ◽  
Significant Inhibition ◽  
Castration Resistant Prostate Cancer ◽  
Orally Bioavailable

381 Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Methods: Here we report an orally bioavailable small molecule AR PROTAC that leads to ubiquitination and degradation of AR. This molecule has been characterized in in vitro degradation and functional assays, DMPK, toxicology and preclinical efficacy studies. Results: This AR PROTAC completely degrades AR in all cell lines tested, with an observed 50% degradation concentration (DC50) < 1 nM. PROTAC-mediated AR degradation suppresses the expression of the AR-target gene PSA, inhibits AR-dependent cell proliferation, and induces potent apoptosis in VCaP cells. The AR PROTAC degrades all clinically relevant mutant AR proteins and retains activity in a high androgen environment. In mouse xenograft studies, greater than 90% AR degradation is observed at a 1 mg/kg PO QD dose. Significant inhibition of tumor growth and AR signaling can be achieved in both an intact and castrate setting. Further, the AR PROTAC demonstrates in vivo efficacy and reduction of oncogenic Erg protein in a long term, castrate, enzalutamide-resistant VCaP tumor model. DMPK and exploratory toxicology studies show robust oral, dose proportional drug exposure in rodent and non-rodent species. Conclusions: In summary, we report preclinical data on an orally bioavailable AR PROTAC degrader that demonstrates efficacy in enzalutamide-resistant prostate cancer.

scholarly journals Preclinical Study Using ABT263 to Increase Enzalutamide Sensitivity to Suppress Prostate Cancer Progression Via Targeting BCL2/ROS/USP26 Axis Through Altering ARv7 Protein Degradation

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 831 ◽  
Author(s):  
Hua Xu ◽  
Yin Sun ◽  
Chi-Ping Huang ◽  
Bosen You ◽  
Dingwei Ye ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Standard Of Care ◽  
Preclinical Study ◽  
Ros Generation ◽  
Castration Resistant Prostate Cancer ◽  
Enzyme Activity Assay ◽  
Ubiquitin Proteasome

Background: The recently developed antiandrogen, Enzalutamide (Enz), has reformed the standard of care for castration resistant prostate cancer (CRPC) patients. However, Enz-resistance inevitably emerges despite success of Enz in prolonging CRPC patients’ survival. Here we found that Enz-resistant prostate cancer (PCa) cells had higher BCL2 expression. We aimed to test whether targeting BCL2 would influence Enz sensitivity of prostate cancer (PCa) and identify the potential mechanism. Methods: The study was designed to target Enz-induced BCL2 with inhibitor ABT263 and test Enz sensitivity in Enz-resistant PCa cells by MTT assay. Cellular reactive oxygen species (ROS) levels were detected with dihydroethidium staining, and in vitro deubiquitinating enzyme activity assay was used to evaluate ubiquitin specific protease 26 (USP26) activity. Results: ABT263 could increase Enz sensitivity in both Enz-sensitive and Enz-resistant PCa cells via inducing ROS generation. Elevated cellular ROS levels might then inhibit USP26 activity to increase the ubiquitination of androgen receptor (AR) and AR splice variant 7 (ARv7) and their ubiquitin/proteasome-dependent degradation, which contributed to the increase of Enz sensitivity. In vivo mouse model also demonstrates that ABT263 will suppress the PCa progression. Conclusion: This study demonstrated that targeting Enz-induced BCL2 with inhibitor ABT263 could increase Enz sensitivity in both Enz-sensitive and Enz-resistant PCa cells through induction of cellular ROS levels and suppression of USP26 activity with a consequent increase of ubiquitin/proteasome-dependent degradation of AR and ARv7 protein expression.

scholarly journals KDM6B is an androgen regulated gene and plays oncogenic roles by demethylating H3K27me3 at cyclin D1 promoter in prostate cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhi Cao ◽  
Xiaolei Shi ◽  
Feng Tian ◽  
Yu Fang ◽  
Jason Boyang Wu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cyclin D1 ◽  
Biological Function ◽  
Malignant Tumors ◽  
Specific Antigen ◽  
Regulation Mechanism ◽  
Castration Resistant Prostate Cancer

AbstractLysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, plays oncogenic or antitumoral roles in malignant tumors depending on the type of tumor cell. However, how this histone modifier affects the progression of prostate cancer (PCa) is still unknown. Here we analyzed sequenced gene expression data and tissue microarray to explore the expression features and prognostic value of KDM6B in PCa. Further, we performed in vitro cell biological experiments and in vivo nude mouse models to reveal the biological function, upstream and downstream regulation mechanism of KDM6B. In addition, we investigated the effects of a KDM6B inhibitor, GSK-J4, on PCa cells. We showed that KDM6B overexpression was observed in PCa, and elevated KDM6B expression was associated with high Gleason Score, low serum prostate-specific antigen level and shorted recurrence-free survival. Moreover, KDM6B prompted proliferation, migration, invasion and cell cycle progression and suppressed apoptosis in PCa cells. GSK-J4 administration could significantly suppress the biological function of KDM6B in PCa cells. KDM6B is involved in the development of castration-resistant prostate cancer (CRPC), and combination of MDV3100 plus GSK-J4 is effective for CRPC and MDV3100-resistant CRPC. Mechanism exploration revealed that androgen receptor can decrease the transcription of KDM6B and that KDM6B demethylates H3K27me3 at the cyclin D1 promoter and cooperates with smad2/3 to prompt the expression of cyclin D1. In conclusion, our study demonstrates that KDM6B is an androgen receptor regulated gene and plays oncogenic roles by promoting cyclin D1 transcription in PCa and GSK-J4 has the potential to be a promising agent for the treatment of PCa.

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