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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
SC912 inhibits AR-V7 activity in castration-resistant prostate cancer by targeting the androgen receptor N-terminal
Qianhui Yi1,2, Xiaojun Han1, Henry G Yu1,2
1Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, McGill University, 3755 Cote-Ste-Catherine, Rd, Montreal, QC, H3T 1E2, Canada.
Abstract:
Androgen deprivation therapies (ADT) are the mainstay treatments for castration-resistant prostate cancer (CRPC). ADT suppresses the androgen receptor (AR) signaling by blocking androgen biosynthesis or inhibiting AR with antiandrogens that target AR's ligand-binding domain (LBD). However, the ADT's effect is short-lived, as the AR signaling inevitably arises again, which is frequently coupled with AR-V7 overexpression. AR-V7 is a truncated form of AR that lacks the LBD, thus being constitutively active in the absence of androgens and irresponsive to AR-LBD-targeting inhibitors. Though compelling evidence has tied AR-V7 to drug resistance in CRPC, pharmacological inhibition of AR-V7 is still an unmet need. Here, we discovered a small molecule, SC912, which binds to full-length AR as well as AR-V7 through AR N-terminal domain (AR-NTD). This pan-AR targeting relies on the amino acids 507-531 in the AR-NTD. SC912 also disrupted AR-V7 transcriptional activity, impaired AR-V7 nuclear localization and DNA binding. In the AR-V7 positive CRPC cells, SC912 suppressed proliferation, induced cell-cycle arrest, and apoptosis. In the AR-V7 expressing CRPC xenografts, SC912 attenuated tumor growth and antagonized intratumoral AR signaling. Together, these results suggested the therapeutic potential of SC912 for CRPC.
Insights
A new drug, SC912, effectively targets both full-length androgen receptor (AR) and the drug-resistant AR-V7 variant in castration-resistant prostate cancer (CRPC). This discovery offers a promising therapeutic strategy for patients with advanced prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Androgen deprivation therapies (ADT) are standard treatments for castration-resistant prostate cancer (CRPC).
- Resistance to ADT often involves the overexpression of androgen receptor variant 7 (AR-V7), which lacks the ligand-binding domain and is unresponsive to current therapies.
- Targeting AR-V7 is a critical unmet need in CRPC treatment.
Purpose of the Study:
- To discover and characterize a novel small molecule inhibitor targeting both full-length AR and AR-V7.
- To evaluate the therapeutic potential of this new agent in preclinical models of CRPC.
Main Methods:
- Identification of a small molecule, SC912, that binds to the N-terminal domain (AR-NTD) of both AR and AR-V7.
- Assessment of SC912's effects on AR-V7 transcriptional activity, nuclear localization, and DNA binding.
- In vitro studies using AR-V7 positive CRPC cell lines to evaluate proliferation, cell-cycle arrest, and apoptosis.
- In vivo studies using CRPC xenograft models expressing AR-V7 to assess tumor growth inhibition and AR signaling antagonism.
Main Results:
- SC912 demonstrated binding to AR and AR-V7 via amino acids 507-531 in the AR-NTD.
- SC912 effectively disrupted AR-V7 transcriptional activity, nuclear localization, and DNA binding.
- In vitro, SC912 suppressed proliferation and induced cell-cycle arrest and apoptosis in AR-V7 positive CRPC cells.
- In vivo, SC912 attenuated tumor growth and antagonized intratumoral AR signaling in AR-V7 expressing CRPC xenografts.
Conclusions:
- SC912 is a novel pan-AR inhibitor targeting both AR and AR-V7.
- SC912 exhibits significant preclinical efficacy in AR-V7 positive CRPC models.
- SC912 holds therapeutic potential for treating patients with advanced castration-resistant prostate cancer, particularly those with AR-V7 expression.
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