Androgen receptor independent acquired mechanisms of resistance to enzalutamide in castration-resistant prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 129-129
Author(s):  
Russell Zelig Szmulewitz ◽  
Steve Kregel ◽  
Masis Isikbay ◽  
Yi Cai ◽  
James Lin Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cell Lines ◽  
Dna Sequences ◽  
Castration Resistant Prostate Cancer ◽  
Testosterone Levels ◽  
Castration Resistant ◽  
Stat Signaling

129 Background: Enzalutamide (MDV3100) is a second generation androgen receptor (AR) antagonist with potent activity in the treatment of castration resistant prostate cancer (CRPC). However, most patients develop resistance and progression of disease; thus there is a critical need to identify novel targetable pathways mechanistically linked to this resistance. Methods: A panel of four prostate cancer cell lines (LAPC-4, LNCaP, VCaP, and CWRR1) was created each with a different AR status that are resistant to MDV3100 by culturing cells long-term less than 6 months in the drug at pharmacologic levels. The MDV3100 resistant (MDV-R) lines were assayed for proliferation, viability, resistance to docetaxel, and tumor take of subcutaneous xenografts. AR expression and ligand binding domain (LBD) DNA sequences were analyzed. Gene expression microarray comparison of resistant and non-resistant parental cell lines was performed. Prostate-specific antigen (PSA) and testosterone levels were analyzed from conditioned media. Results: Cell lines demonstrated heterogeneous growth characteristics.In vivo studies depicted increased or unaltered tumor take and growth in castrate athymic mice. In some cell lines growth was increased in vitro when drug was withdrawn; yet this growth was inhibited by physiological testosterone levels, both in vitro and in vivo. MDV-R cells remained sensitive to docetaxel in vitro and had increased levels of ARmRNA. However, total AR protein levels were lower or unchanged than the parental lines, with evidence for increased truncated forms of AR. The AR LBD acquired no new mutations. Secreted PSA was lower in all but one MDV-R line. Gene expression analyses demonstrated strong upregulation of IGFBP3 in all MDV-R cells. Pathway analysis implicated increased IGF and JAK/STAT signaling whereas mammalian target of rapamycin (mTOR) signaling was decreased. Conclusions: Although AR-mediated pathways contribute to enzalutamide resistance, a broader approach across several cell lines suggests that there may be even a greater contribution from pleiotropic, non-AR mediated mechanisms. Such mechanisms may include IGF signaling, JAK/STAT signaling and modulation of mTOR.

Testosterone levels and androgen receptor copy number variations in castration‐resistant prostate cancer treated with abiraterone or enzalutamide

The Prostate ◽  
2019 ◽  
Vol 79 (11) ◽  
pp. 1211-1220 ◽  
Author(s):  
Cristian Lolli ◽  
Delia Lisi ◽  
Vincenza Conteduca ◽  
Giorgia Gurioli ◽  
Emanuela Scarpi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Copy Number ◽  
Copy Number Variations ◽  
Castration Resistant Prostate Cancer ◽  
Testosterone Levels ◽  
Castration Resistant

scholarly journals Reactivation of Androgen Receptor–Regulated TMPRSS2:ERG Gene Expression in Castration-Resistant Prostate Cancer

2009 ◽  
Vol 69 (15) ◽  
pp. 6027-6032 ◽  
Author(s):  
Changmeng Cai ◽  
Hongyun Wang ◽  
Youyuan Xu ◽  
Shaoyong Chen ◽  
Steven P. Balk
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Androgen Receptor ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

scholarly journals IL1B loss is associated with increased AR activity in castration-resistant prostate cancer

2021 ◽  
Author(s):  
Wisam N. Awadallah ◽  
Jagpreet S. Nanda ◽  
Sarah E. Kohrt ◽  
Magdalena M Grabowska
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cancer Cells ◽  
Marker Gene ◽  
Neuroendocrine Differentiation ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Castration Resistant ◽  
Expression And Activity

Castration-resistant prostate cancer represents a continuum of phenotypes, including tumors with high levels of androgen receptor (AR) expression and activity and those which do not express AR and rely on alternative pathways for survival. The process by which AR-positive prostate cancer cells and tumors lose AR expression and acquire neuroendocrine features is referred to as neuroendocrine differentiation. Numerous therapies and exposures have been demonstrated to induce neuroendocrine differentiation in vitro, including the pro-inflammatory cytokine, interleukin 1 beta (IL-1β), encoded by the gene IL1B. The purpose of our studies was to determine the relationship between the expression and activity of AR in relationship to IL-1β and IL1B in prostate cancer. We performed analysis of de-identified human clinical data and generated prostate cancer cell lines with overexpression or knockout of IL1B. In primary prostate cancer, higher expression of IL1B predicts longer time to biochemical recurrence. In metastatic castration-resistant prostate cancer, IL1B expression is decreased and inversely correlates with AR and AR-target gene expression and AR activity, while positively correlating with the neuroendocrine prostate cancer (NEPC) score and neuroendocrine marker gene expression. In vitro, we report that AR-positive castration-resistant prostate cancer cells (C4-2B, 22Rv1) secrete IL-1β, and knockout of IL1B in these cells results in increased AR activity, in the presence and absence of dihydrotestosterone (DHT). Importantly, knockout of IL1B prevented AR attrition during androgen-deprivation. Taken together, our studies demonstrate that loss of IL1B in AR-positive castration-resistant prostate cancer cells can increase and maintain AR activity in the absence of androgens, suggesting another potential mechanism of high AR activity in castration-resistant prostate cancer.

scholarly journals Development of Novel Chalcone Analogs as Potential Multi-Targeted Therapies for Castration-Resistant Prostate Cancer

2021 ◽  
Author(s):  
Ola Hussein ◽  
Feras Alali ◽  
Ala‐Eddin Al Mustafa ◽  
Ashraf Khalil
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
In Vivo Studies ◽  
Treatment Modalities ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Biological Studies ◽  
In Silico Admet

Prostate cancer (PCa) is the second most frequently diagnosed malignancy, as well as a leading cause of cancer-related mortality in men globally. Despite the initial response to hormonal targeted therapy, the majority of patients ultimately progress to a lethal form of the disease, castration-resistant prostate cancer (CRPC). Therefore, the objective of this study was to discover and develop novel treatment modalities for CRPC. Chalcones are among the highly attractive scaffolds being investigated for their antitumor activities. A library of 26 chalcone analogs were designed, synthesized and evaluated as potential therapies for CRPC. The design was guided by in-silico ADMET prediction in which analogs with favorable drug-likeness properties were prioritized. The new compounds were synthesized, purified and characterized by extensive structural elucidation studies. The compounds in vitro cytotoxicity was evaluated against two androgen receptor (AR)-negative prostate cancer cell lines (PC3 and DU145). Among the tested compounds, pyridine containing analogs (13, 15 and 16) showed potent antiproliferative activities with IC50 values ranging between 4.32-6.47 µM against PC3 and DU145 cell lines. Detailed biological studies of the lead molecule 16 revealed that it can significantly induce apoptosis through upregulation of Bax and downregulation of Bcl-2. In addition, compound 16 potently inhibited colony formation and reduced cell migration of AR-negative PCa cell lines (PC3 and DU145). The molecular pathway analysis showed that the anticancer activity of compound 16 is associated with blocking of ERK1/2 and Akt activities. Furthermore, compound 16 inhibited angiogenesis in the chick chorioallantoic membrane (CAM) model as compared to control. Structure-activity relationship study revealed that the cytotoxicity could dramatically improve via changing the methoxylation pattern by more than 2-folds (IC50 << 2.5 μM). These results indicate that pyridine-based chalcones could serve as promising lead molecules for the treatment of CRPC; thus, further in vitro and in vivo studies are warranted.

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.

A circulating tumor cell specific RNA assay for assessment of androgen receptor signaling inhibitor sensitivity in metastatic castration-resistant prostate cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5059-5059
Author(s):  
Pai-Chi Teng ◽  
Yu Jen Jan ◽  
Junhee Yoon ◽  
Pin-Jung Chen ◽  
Jie-Fu Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Drug Resistance ◽  
Androgen Receptor ◽  
Tumor Cell ◽  
Cell Lines ◽  
Circulating Tumor Cell ◽  
Z Score ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Receptor Signaling ◽  
Castration Resistant

5059 Background: Our objective is to develop a circulating tumor cell (CTC)-RNA assay for characterizing clinically relevant RNA signatures for the assessment of androgen receptor signaling inhibitors (ARSIs) sensitivity in metastatic castration-resistant prostate cancer (mCRPC) patients. Methods: We developed NanoVelcro CTC-RNA Assay by combining Thermoresponsive(TR)-NanoVelcro CTC purification system with NanoString nCounter platform for CTC purification and RNA analysis. Based on the well-validated, tissue-based Prostate Cancer Classification System (PCS), we selected the most aggressive and ARSI-resistant subtype- the PCS1, for CTC analysis. We applied a rigorous bioinformatic process to develop a CTC-PCS1 panel that is specific to PC CTCs. We validated NanoVelcro CTC-RNA Assay and CTC-PCS1 panel with PC cell lines to demonstrate sensitivity and specificity of the PCS1 Z score (the likelihood estimate of the PCS1 subtype) for identifying PCS1 subtype and ARSI resistance. We then selected 31 blood samples from 23 PC patients receiving ARSIs to test in our assay. The PCS1 Z score of each sample was computed and compared with ARSI treatment sensitivity. Results: We established a 16-gene CTC-PCS1 panel that consists of CTC-specific RNA signatures. The validation studies using PC cell lines showed that the assay can detect the RNA transcripts with high sensitivity and scalability in the range of 1-100 cells. We also showed that the genes in CTC-PCS1 panel is highly expressed in PC cells. We further demonstrated that the CTC-PCS1 panel is highly specific in identifying PCS1-like samples, and the high PCS1 Z score is associated with ARSI resistance. In patient bloods, ARSI-resistant samples (ARSI-R, n=14) had significantly higher PCS1 Z scores as compared with ARSI-sensitive samples (ARSI-S, n=17) (Rank-sum test, P=0.003). In 8 patients who were initially sensitive to ARSI (ARSI-S) and later developed resistance (ARSI-R), we found that the PCS1 Z score increased from the time of ARSI-S to the time of ARSI-R (Pairwise T-test, P=0.016). Conclusions: Using our new methodology, we developed a first-in-class CTC-RNA assay and demonstrated the feasibility of transforming clinically-relevant tissue-based RNA profiling into CTC tests. This approach allows for detecting RNA expression relevant to clinical drug resistance in a non-invasive fashion, which can facilitate patient-specific treatment selection and early detection of drug resistance- a goal in precision oncology.

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