scholarly journals Combination of carmustine and selenite effectively inhibits tumor growth by targeting androgen receptor, androgen receptor-variants, and Akt in preclinical models: New hope for patients with castration resistant prostate cancer

2016 ◽  
Vol 139 (7) ◽  
pp. 1632-1647 ◽  
Author(s):  
Vijayalakshmi Thamilselvan ◽  
Mani Menon ◽  
Sivagnanam Thamilselvan
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Tumor Growth ◽  
Castration Resistant Prostate Cancer ◽  
Preclinical Models ◽  
Castration Resistant ◽  
Androgen Receptor Variants

scholarly journals Novel Selective Agents for the Degradation of Androgen Receptor Variants to Treat Castration-Resistant Prostate Cancer

2017 ◽  
Vol 77 (22) ◽  
pp. 6282-6298 ◽  
Author(s):  
Suriyan Ponnusamy ◽  
Christopher C. Coss ◽  
Thirumagal Thiyagarajan ◽  
Kate Watts ◽  
Dong-Jin Hwang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Selective Agents ◽  
Androgen Receptor Variants

Blocking GRP/GRP-R Signaling Decreases Expression of Androgen Receptor Splice Variants and Inhibits Tumor Growth in Castration-resistant Prostate Cancer

2021 ◽  
Author(s):  
Thomas C Case ◽  
Alyssa Merkel ◽  
Marisol Ramirez-Solano ◽  
Qi Liu ◽  
Julie A Sterling ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Fluorescent Protein ◽  
Splice Variants ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Reporter Vector

Abstract Background: Clinical management of castration-resistant prostate cancer (CRPC) resulting from androgen deprivation therapy (ADT) remains challenging. Previously, we have reported that long-term ADT increases the neuroendocrine (NE) hormone – Gastrin Releasing Peptide (GRP) and its receptor (GRP-R) expression in prostate cancer (PC) cells. Further, we demonstrated that activation of GRP/GRP-R signaling increases androgen receptor (AR) splice variants (ARVs) expression through activating NF-κB signaling thereby contributing cancer progression to CRPC. Most importantly, as a cell surface protein, GRP-R is easily targeted by drugs to block GRP/GRP-R signaling. Here, we aim to investigate if blocking GRP/GRP-R signaling by targeting GRP-R using GRP-R antagonist is sufficient to control CRPC progression, including in therapy-induced (t) neuroendocrine prostate cancer (tNEPC). Methods: Bone-growing NEPC cells were generated by treating androgen dependent LNCaP PC cells with anti-androgen (MDV3100) for more than 3 months. RC-3095, a selective GRP-R antagonist, was used for blocking GRP/GRP-R signaling. The NGL vector [a NF-kB responsive reporter vector which has Luciferase and Green Fluorescent Protein (GFP) reporter genes] was used to measure NF-kB activity and the ARR2PB-Luc vector (an AR responsive reporter vector) was used to measure AR activity in the PC cells. For in vivo experiments, the effect of RC-3095 on CRPC was observed in subcutaneous CRPC and bone-growing tNEPC tumor models.Results: Our studies show that blocking GRP/GRP-R signal by targeting GRP-R using RC-3095 efficiently inhibits NF-κB activity and ARVs (AR-V7) expression in CRPC and tNEPC cells. In addition, blocking of GRP/GRP-R signaling by targeting GRP-R can sensitize CRPC cells to anti-androgen treatment. Further, preclinical animal studies indicate combination of GRP-R antagonist (targeting ARVs) with anti-androgen [targeting full-length AR (AR-FL)] is sufficient to inhibit CRPC and tNEPC tumor growth.Conclusion: Our findings strongly indicate that blocking of GRP/GRP-R signaling in combination with ADT is a potential new approach to control CRPC tumor growth, including ADT induced tNEPC.

Tumor response and adaptation to CYP17 inhibition in prostate cancer: Induction of steroidogenesis and androgen receptor splice variants.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 18-18
Author(s):  
E. A. Mostaghel ◽  
B. Marck ◽  
A. M. Matsumoto ◽  
P. Nelson ◽  
R. Vessella ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Tumor Growth ◽  
Median Survival ◽  
Splice Variants ◽  
Late Time ◽  
Castration Resistant Prostate Cancer ◽  
Time Points ◽  
Castration Resistant ◽  
Androgen Levels

18 Background: Abiraterone is a novel inhibitor of the steroidogenic enzyme CYP17 and suppresses tumor growth in patients with castration-resistant prostate cancer (CRPC). The efficacy of abiraterone in suppressing tumor androgens or mechanisms of resistance to abiraterone are not known. Methods: Human CRPC xenografts LuCaP 23 and LuCaP 35 grown in castrated male mice were treated with abiraterone to determine effects on tumor growth and tumor androgen levels. Tumor gene expression measurements were obtained to delineate mechanisms of abiraterone resistance. Results: Abiraterone i.p. for 21 days improved survival (time to tumor size 750 mm3) vs vehicle control (VC) in LuCaP 35 (HR 3.8 [95% CI 3.1-53.7] median survival 39 vs 18 days) and LuCap 23 (HR 2.4 [1.43-10.24] median survival 24 vs. 14 days). Greater anti-tumor activity correlated with superior tumor androgen suppression. Tumor testosterone was strongly suppressed in both LuCaP35 (0.20 + 0.24 vs VC 0.69 + 0.36 pg/mg) and LuCaP 23 (0.07 + 0.11 vs VC 0.49 + 0.22 pg/mg). DHT levels were also markedly suppressed in LuCaP35 (1.17 + 1.46 vs VC 3.49 + 1.81pg/mg). In contrast, DHT levels in LuCap23 were unchanged early (day 7-21) and only partially suppressed at longer time points (VC 5.73 + 1.88; early 5.31 + 2.69; late 2.82 + 2.27 pg/mg). Expression of the abiraterone target CYP17 was upregulated in both xenografts (LuCaP23 2.5 fold, p<0.0001; LuCap35 2.9 fold, p=0.028). Overall, LuCap23 appeared resistant to suppression of tumor androgens due to induction of steroidogenic transcripts (including STAR, CYP11, HSD3B1 and AKR1C3) without statistically significant increases in androgen receptor (AR). In contrast, LuCap35 demonstrated strong induction of transcripts for AR and AR splice variants (AR 3.8 fold, p<0.0001, V7 AR splice variant 3.7 fold, p<0.0001), with induction of steroidogenic transcripts only at late time points. Conclusions: Abiraterone treatment suppressed intratumoral androgen levels and reduced growth of CRPC xenografts. Abiraterone resistance may occur through upregulation of the abiraterone target CYP17, and/or the induction of AR and AR splice variants that confer ligand-independent AR trans-activation. [Table: see text]

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