Abstract 1918: Patient-derived hormone-naive prostate cancer xenograft models revealGRB10as an AR-repressed gene driving the development of castration-resistant prostate cancer

2018 ◽  
Author(s):  
Jun Hao ◽  
Xinpei Ci ◽  
Hui Xue ◽  
Rebecca Wu ◽  
Xin Dong ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Xenograft Models

scholarly journals Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer

Nature ◽  
2021 ◽  
Author(s):  
Lanbo Xiao ◽  
Abhijit Parolia ◽  
Yuanyuan Qiao ◽  
Pushpinder Bawa ◽  
Sanjana Eyunni ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cell ◽  
Regulatory Elements ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Super Enhancer ◽  
Potent Inhibition ◽  
Promising Therapeutic Approach ◽  
Atpase Subunits ◽  
Xenograft Models

AbstractThe switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling1 and is altered in over 20% of cancers2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.

scholarly journals A molecule inducing androgen receptor degradation and selectively targeting prostate cancer cells

2019 ◽  
Vol 2 (4) ◽  
pp. e201800213 ◽  
Author(s):  
Serge Auvin ◽  
Harun Öztürk ◽  
Yusuf T Abaci ◽  
Gisele Mautino ◽  
Florence Meyer-Losic ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Ex Vivo ◽  
Castration Resistant Prostate Cancer ◽  
Clinical Issue ◽  
Castration Resistant ◽  
Clinical Resistance ◽  
Xenograft Models ◽  
Prostate Cancers

Aberrant androgen signaling drives prostate cancer and is targeted by drugs that diminish androgen production or impede androgen–androgen receptor (AR) interaction. Clinical resistance arises from AR overexpression or ligand-independent constitutive activation, suggesting that complete AR elimination could be a novel therapeutic strategy in prostate cancers. IRC117539 is a new molecule that targets AR for proteasomal degradation. Exposure to IRC117539 promotes AR sumoylation and ubiquitination, reminiscent of therapy-induced PML/RARA degradation in acute promyelocytic leukemia. Critically, ex vivo, IRC117539-mediated AR degradation induces prostate cancer cell viability loss by inhibiting AR signaling, even in androgen-insensitive cells. This approach may be beneficial for castration-resistant prostate cancer, which remains a clinical issue. In xenograft models, IRC117539 is as potent as enzalutamide in impeding growth, albeit less efficient than expected from ex vivo studies. Unexpectedly, IRC117539 also behaves as a weak proteasome inhibitor, likely explaining its suboptimal efficacy in vivo. Our studies highlight the feasibility of AR targeting for degradation and off-target effects’ importance in modulating drug activity in vivo.

New combination therapies for castration-resistant prostate cancer

2019 ◽  
Author(s):  
Mitchell G Lawrence ◽  
Laura H Porter ◽  
Daisuke Obinata ◽  
Shahneen Sandhu ◽  
Luke A Selth ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
New Combination ◽  
Combination Therapies ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant
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