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MR Molecular Imaging of Prostate Cancer with a Small Molecular CLT1 Peptide Targeted Contrast Agent
Published on: September 3, 2013
An imaging agent to detect androgen receptor and its active splice variants in prostate cancer
Yusuke Imamura1, Amy H Tien1, Jinhe Pan2
1Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, Canada.
Abstract:
Constitutively active splice variants of androgen receptor (AR-Vs) lacking ligand-binding domain (LBD) are a mechanism of resistance to androgen receptor LBD-targeted (AR LBD-targeted) therapies for metastatic castration-resistant prostate cancer (CRPC). There is a strong unmet clinical need to identify prostate cancer patients with AR-V-positive lesions to determine whether they will benefit from further AR LBD-targeting therapies or should receive taxanes or investigational drugs like EPI-506 or galeterone. Both EPI-506 (NCT02606123) and galeterone (NCT02438007) are in clinical trials and are proposed to have efficacy against lesions that are positive for AR-Vs. AR activation function-1 (AF-1) is common to the N-terminal domains of full-length AR and AR-Vs. Here, we provide proof of concept for developing imaging compounds that directly bind AR AF-1 to detect both AR-Vs and full-length AR. 123I-EPI-002 had specific binding to AR AF-1, which enabled direct visualization of CRPC xenografts that express full-length AR and AR-Vs. Our findings highlight the potential of 123I-EPI-002 as an imaging agent for the detection of full-length AR and AR-Vs in CRPC.
Insights
New imaging agents targeting androgen receptor activation function-1 (AR AF-1) can visualize prostate cancer lesions. This helps identify patients who may benefit from specific therapies, guiding treatment for metastatic castration-resistant prostate cancer (CRPC).
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Constitutively active androgen receptor splice variants (AR-Vs) confer resistance to standard therapies in metastatic castration-resistant prostate cancer (CRPC).
- Identifying patients with AR-V-positive lesions is crucial for guiding treatment decisions between continued androgen receptor ligand-binding domain (AR LBD)-targeted therapies or alternative treatments like taxanes or investigational drugs.
- Current diagnostic methods lack specificity for detecting AR-V-positive tumors.
Purpose of the Study:
- To develop and validate a novel imaging agent targeting the androgen receptor activation function-1 (AR AF-1) domain.
- To demonstrate the potential of this agent for visualizing both full-length AR and AR-Vs in CRPC models.
- To establish proof of concept for a new diagnostic tool to guide CRPC treatment strategies.
Main Methods:
- Synthesis and characterization of the radioiodinated compound 123I-EPI-002, designed to bind AR AF-1.
- In vivo imaging studies using CRPC xenograft models expressing either full-length AR or AR-Vs.
- Assessment of specific binding of 123I-EPI-002 to AR AF-1 in tumor tissues.
Main Results:
- 123I-EPI-002 demonstrated specific binding to the AR AF-1 domain.
- Direct visualization of CRPC xenografts expressing both full-length AR and AR-Vs was achieved using 123I-EPI-002.
- The imaging agent successfully detected AR-positive lesions in vivo.
Conclusions:
- 123I-EPI-002 shows promise as a molecular imaging agent for detecting both full-length AR and AR-Vs in CRPC.
- This novel imaging approach could aid in patient stratification for targeted therapies and clinical trials.
- Further development of AR AF-1-targeting agents may improve diagnostic capabilities in prostate cancer management.
