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Updated: Aug 22, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Expression patterns of potential targets for antibody-directed therapy in metastatic castration-resistant prostate
Tanja C van Dijk1, Marcel Smid1, Debbie G J Robbrecht1
1Department of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, Rotterdam 3015 GD, the Netherlands.
Introduction:
Survival in metastatic castration-resistant prostate cancer (mCRPC) patients remains limited and treatment is complicated by tumor heterogeneity. As antibody-based therapeutics emerge, identifying actionable antigen targets and patient subgroups most likely to benefit is essential.
Materials & Methods:
Gene expression of 62 antibody-targetable proteins was analyzed in 296 mCRPC biopsies. These genes encode proteins targeted by approved or investigational antibody-based cancer therapeutics. Associations between target expression with genomic classifications and transcriptomic subtypes were evaluated. Target expression was also assessed in tumors with low expression of established mCRPC targets. Subgroup-specific targets were validated in an independent cohort and single-cell transcriptomics.
Results:
Established targets KLK2, FOLH1 (PSMA) and STEAP1 showed the highest median expression across the cohort. Target expression did not correlate with genomic classifications, including homologous recombination deficiency, microsatellite instability, CDK12, TP53, PTEN or AR alterations Target expression did associate with transcriptomic subtypes: CRPC-AR (driven by androgen receptor-signaling) and CRPC-SCL (stem cell-like features, AP-1/YAP/TAZ-driven), displayed the highest expression of multiple targets, including KLK2, FOLH1, and SLC44A4. CRPC-NE (neuroendocrine phenotype) showed heterogeneous expression, with high CD46 expression, whereas CRPC-WNT (Wnt-signaling driven) generally showed low target expression. Notably, CD46 was highly expressed in tumors with low KLK2, FOLH1, and STEAP1 expression, a subgroup associated with poor prognosis.
Conclusions:
Although several antibody targets showed broad expression in mCRPC-tumors, expression varied by transcriptomic subtype. Subgroups such as CRPC-WNT expressed fewer targets, suggesting the need for alternative therapeutic strategies. CD46 emerged as a promising target, with wide expression across multiple subtypes, including clinically challenging CRPC-NE and mCRPC tumors lacking expression of established targets.
Insights
Identifying antibody targets in metastatic castration-resistant prostate cancer (mCRPC) is crucial. CD46 is a promising target across mCRPC subtypes, especially those lacking established targets.
Area of Science:
- Oncology
- Translational Research
- Genomics
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) presents limited survival and treatment challenges due to tumor heterogeneity.
- Emerging antibody therapeutics necessitate identification of actionable antigen targets and patient subgroups for effective treatment.
Purpose of the Study:
- To analyze gene expression of antibody-targetable proteins in mCRPC biopsies.
- To associate target expression with genomic and transcriptomic classifications.
- To identify and validate subgroup-specific targets, including in tumors with low expression of established targets.
Main Methods:
- Gene expression analysis of 62 antibody-targetable proteins in 296 mCRPC biopsies.
- Evaluation of associations between target expression and genomic/transcriptomic classifications.
- Validation of subgroup-specific targets in an independent cohort and single-cell transcriptomics.
Main Results:
- Established targets KLK2, FOLH1 (PSMA), and STEAP1 showed high median expression.
- Target expression did not correlate with genomic classifications but associated with transcriptomic subtypes (CRPC-AR, CRPC-SCL, CRPC-NE, CRPC-WNT).
- CD46 was highly expressed in CRPC-NE and in tumors lacking established targets, indicating potential as a target in poor-prognosis subgroups.
Conclusions:
- Antibody target expression in mCRPC varies significantly by transcriptomic subtype.
- CRPC-WNT subgroup showed limited target expression, suggesting a need for alternative therapeutic strategies.
- CD46 is a promising pan-subtype target, particularly for clinically challenging mCRPC tumors lacking established targets.
