Prior long response to androgen deprivation predicts response to next-generation androgen receptor axis targeted drugs in castration resistant prostate cancer

2015 ◽  
Vol 51 (14) ◽  
pp. 1946-1952 ◽  
Author(s):  
Yohann Loriot ◽  
Jean-Christophe Eymard ◽  
Anna Patrikidou ◽  
Ecaterina Ileana ◽  
Christophe Massard ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Androgen Deprivation ◽  
Targeted Drugs ◽  
Next Generation ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

scholarly journals Next-generation androgen receptor inhibitors in non-metastatic castration-resistant prostate cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592097813
Author(s):  
Pernelle Lavaud ◽  
Clément Dumont ◽  
Constance Thibault ◽  
Laurence Albiges ◽  
Giulia Baciarello ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Androgen Receptor ◽  
Androgen Deprivation Therapy ◽  
Androgen Deprivation ◽  
Next Generation ◽  
Castration Resistant Prostate Cancer ◽  
Free Survival ◽  
Castration Resistant ◽  
Recent Advances

Until recently, continuing androgen deprivation therapy (ADT) and closely monitoring patients until evolution towards metastatic castration-resistant prostate cancer (CRPC) were recommended in men with non-metastatic CRPC (nmCRPC). Because delaying the development of metastases and symptoms in these patients is a major issue, several trials have investigated next-generation androgen receptor (AR) axis inhibitors such as apalutamide, darolutamide, and enzalutamide in this setting. This review summarizes the recent advances in the management of nmCRPC, highlighting the favourable impact of next-generation AR inhibitors on metastases-free survival, overall survival and other clinically meaningful endpoints.

Earlier use of androgen receptor-axis-targeted drugs may improve overall survival in patients with non-metastatic castration-resistant prostate cancer

The Prostate ◽  
2018 ◽  
Vol 78 (10) ◽  
pp. 766-772 ◽  
Author(s):  
Keiichiro Mori ◽  
Takahiro Kimura ◽  
Kagenori Ito ◽  
Hajime Onuma ◽  
Masatoshi Tanaka ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Androgen Receptor ◽  
Targeted Drugs ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Degradation of Androgen Receptor through Small Molecules for Prostate Cancer

2018 ◽  
Vol 18 (7) ◽  
pp. 652-667 ◽  
Author(s):  
Raoling Ge ◽  
Xi Xu ◽  
Pengfei Xu ◽  
Lei Li ◽  
Zhiyu Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Small Molecules ◽  
Androgen Deprivation Therapy ◽  
Resistance Mechanism ◽  
Androgen Deprivation ◽  
High Expression ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Androgen Receptor Antagonists

Prostate cancer is the most common carcinoma among aged males in western countries and more aggressive and lethal castration resistant prostate cancer often occurs after androgen deprivation therapy. The high expression of androgens and androgen receptor is closely related to prostate cancer. Efficient androgen receptor antagonists, such as enzalutamide and ARN-509, could be employed as potent anti-prostate cancer agents. Nevertheless, recent studies have revealed that F876L mutation in androgen receptor converts the action of enzalutamide and ARN-509 from an antagonist to agonist, so that novel strategies are urgent to address this resistance mechanism. In this review, we focus on the discussion about some novel strategies, which targets androgen receptor mainly through the degrading pathway as potential treatments for prostate cancer.

Next generation N-terminal domain androgen receptor inhibitors with improved potency and metabolic stability in castration-resistant prostate cancer models.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 220-220
Author(s):  
Ronan Le Moigne ◽  
Han-Jie Zhou ◽  
Nasrin R Mawji ◽  
C. Adriana Banuelos ◽  
Jun Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Metabolic Stability ◽  
Next Generation ◽  
Castration Resistant Prostate Cancer ◽  
Terminal Domain ◽  
Castration Resistant ◽  
Target Activity

220 Background: EPI-506, pro-drug of EPI-002, was a first-in-class oral small molecule from the Aniten family of compounds, which inhibit androgen receptor (AR) activity by binding to the N-terminal domain of the AR. EPI-506 was tested in a Phase 1 study in men with metastatic castration-resistant prostate cancer (mCRPC) resistant to current therapies and demonstrated a favorable tolerability profile with signs of moderate efficacy. Metabolic vulnerabilities in the chemical scaffold of EPI-506 were identified and new Aniten molecules, EPI-7170 and EPI-7245 , with improved potency, metabolic stability and pharmaceutical properties have been generated. Methods: Chemical structure activity relationships were developed in order to increase molecule potency in cellular and in vivo assays, while metabolic stability improvements were assessed in in vitro ADME assays and in animal pharmacokinetic studies. In addition, the on-target activity and selectivity was also optimized using a variety of cellular experiments. Results: Next generation Anitens demonstrated a 10-20 fold improvement on AR-driven cellular potency, with IC50’s of 0.5-1 uM when compared to 10-12 uM for EPI-002. In vitro proliferation assays demonstrated on target activity, with an IC50 ~ 2 uM in LNCaP and > 10 uM in the AR-independent cell model PC-3. EPI-7170 was also active in AR-V7-driven LNCaP95 cells. The antiproliferative effect was in alignment with the inhibitory effect on a subset of AR driven genes. In vivo activity in castrated mice bearing LNCaP tumors showed tumor growth inhibition of approximately 70%. While EPI-7170 represents a major advance, subsequent chemistry efforts led to the generation of EPI-7245 and other next generation Anitens which exhibit IC50’s < 500 nM and favorable ADME and PK profiles. Conclusions: Promising next-generation Aniten compounds have been identified. Major chemistry efforts led to the identification of several Anitens with > 10-20 fold improvements in cellular potency compared to EPI-506 which are also metabolically stable. IND-selection preclinical studies are underway on the most promising Aniten’s with an IND submission planned shortly.

VAL 201 — An Inhibitor of Androgen Receptor-associated Src and a Potential Treatment of Castration-resistant Prostate Cancer

2012 ◽  
Vol 08 (01) ◽  
pp. 32
Author(s):  
Ferdinando Auricchio ◽  
Antimo Migliaccio ◽  
◽  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Receptor Tyrosine Kinase ◽  
Metastatic Prostate Cancer ◽  
Treatment Options ◽  
Androgen Deprivation ◽  
Castration Resistant Prostate Cancer ◽  
Signal Transduction Protein ◽  
Castration Resistant ◽  
The Us

Prostate cancer is the second leading cause of cancer death in men in the US. The initial treatment of metastatic prostate cancer is androgen deprivation (castration) therapy and this is achieved through either surgical or medical castration, however these therapies are also associated with undesirable side effects including impotence, tumour flare and loss of bone mass. Over time, nearly all patients with metastatic disease become resistant to androgen deprivation, progressing to castration-resistant prostate cancer (CRPC), and at this stage of the disease the prognosis is extremely poor (<50 % survival at two years). Currently there are few treatment options for CRPC. Only four have been found to extend survival and none are curative. Effective treatment of CRPC is a major unmet clinical need, and the identification of alternative therapeutic targets is an active focus of research. In this article we discuss the development of a new agent, Val 201 as a potential future treatment for CRPC. VAL 201 targets the association of androgen receptor with Src, a non-receptor tyrosine kinase signal-transduction protein that is important in tumour cell proliferation, and represents a novel and exciting approach for cancer chemotherapy.

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