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A New Technique for Treating Low-risk Prostate Cancer—Super Active Surveillance
Published on: November 7, 2025
New therapeutic approach to suppress castration-resistant prostate cancer using ASC-J9 via targeting androgen
Kuo-Pao Lai1, Chiung-Kuei Huang, Yu-Jia Chang
1Department of Pathology, Urology, and Radiation Oncology, the George Whipple Laboratory for Cancer Research, University of Rochester Medical Center, Rochester, New York 14642, USA.
Abstract:
Using androgen receptor (AR) knockout mice to determine AR functions in selective prostate cancer (PCa) cells, we determined that AR might play differential roles in various cell types, either to promote or suppress PCa development/progression. These observations partially explain the failure of current androgen deprivation therapy (ADT) to reduce/prevent androgen binding to AR in every cell. Herein, we identified the AR degradation enhancer ASC-J9, which selectively degrades AR protein via interruption of the AR-AR selective coregulator interaction. Such selective interruption could, therefore, suppress AR-mediated PCa growth in the androgen-sensitive stage before ADT and in the castration-resistant stage after ADT. Mechanistic dissection suggested that ASC-J9 could activate the proteasome-dependent pathway to promote AR degradation through the enhanced association of AR-Mdm2 complex. The consequences of ASC-J9-promoted AR degradation included reduced androgen binding to AR, AR N-C terminal interaction, and AR nuclear translocation. Such inhibitory regulation could then result in suppression of AR transactivation and AR-mediated cell growth in eight different mouse models, including intact or castrated nude mice xenografted with androgen-sensitive LNCaP cells or androgen-insensitive C81 cells and castrated nude mice xenografted with castration-resistant C4-2 and CWR22Rv1 cells, and TRAMP and Pten(+/-) mice. These results demonstrate that ASC-J9 could serve as an AR degradation enhancer that effectively suppresses PCa development/progression in the androgen-sensitive and castration-resistant stages.
Insights
A novel compound, ASC-J9, selectively degrades androgen receptor (AR) protein, offering a new strategy to suppress prostate cancer (PCa) growth. This approach works in both early and advanced stages of PCa, even after standard treatments fail.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and progression.
- Current androgen deprivation therapy (ADT) is not universally effective due to AR's complex roles in different cell types.
- Understanding AR's differential functions is crucial for developing more effective PCa treatments.
Purpose of the Study:
- To identify novel therapeutic agents targeting AR in prostate cancer.
- To investigate the mechanism of action of ASC-J9 as an AR degradation enhancer.
- To evaluate the efficacy of ASC-J9 in suppressing PCa growth in various preclinical models.
Main Methods:
- Utilized AR knockout mice to study AR functions in PCa.
- Identified and characterized ASC-J9 as a selective AR degradation enhancer.
- Investigated the molecular mechanisms of ASC-J9, including proteasome pathway activation and AR-Mdm2 complex formation.
- Assessed ASC-J9 efficacy in multiple PCa mouse models, including androgen-sensitive and castration-resistant xenografts.
Main Results:
- ASC-J9 selectively degrades AR protein by interrupting AR-coregulator interactions.
- ASC-J9 promotes AR degradation via the proteasome-dependent pathway, enhancing AR-Mdm2 complex association.
- ASC-J9 reduces androgen binding, AR N-C terminal interaction, and AR nuclear translocation.
- ASC-J9 effectively suppresses AR transactivation and AR-mediated cell growth in diverse PCa models.
Conclusions:
- ASC-J9 is a potent AR degradation enhancer with therapeutic potential for prostate cancer.
- ASC-J9 demonstrates efficacy in suppressing PCa growth during both androgen-sensitive and castration-resistant stages.
- ASC-J9 represents a promising novel therapeutic strategy for overcoming ADT resistance in PCa.
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