Beyond PSMA: theranostic cell surface targets in metastatic prostate cancer

Area of Science:

• Oncology
• Radiochemistry
• Molecular Imaging

Background:

• Metastatic prostate cancer (mPC) remains a significant cause of cancer mortality.
• Treatment resistance to androgen receptor pathway inhibitors (ARPIs) and chemotherapy leads to heterogeneous cell surface antigen expression in mPC.
• This heterogeneity presents opportunities for novel diagnostic imaging and targeted therapeutics.

Purpose of the Study:

• To review emerging cell surface theranostic targets and agents for metastatic prostate cancer.
• To identify novel targets for both diagnostic imaging (e.g., PET) and therapeutic interventions.
• To discuss the relevance of these targets in the context of treatment resistance.

Main Methods:

• A comprehensive literature search was conducted in March 2025 using PubMed and ClinicalTrials.gov.
• Keywords included "Prostate Cancer", "CRPC" (castration-resistant prostate cancer), and "Cell Surface Targets".
• Searches focused on identifying cell surface targets with ongoing or completed clinical trials for imaging and/or therapeutic agents.

Main Results:

• The review identified 13 novel cell surface targets with substantial supporting literature.
• Targets were categorized based on relevance to androgen receptor (AR)-positive and AR-negative mPC, including neuroendocrine prostate cancer (NEPC).
• Information on ongoing and completed clinical trials utilizing these targets for imaging and therapy was compiled.

Conclusions:

• Multiple prostate cancer cell surface markers are emerging as promising theranostic targets.
• For patients progressing on or ineligible for PSMA-targeting therapies, expanding cell surface-targeting strategies is essential.
• Therapeutic modalities include antibody-drug conjugates (ADCs), cellular therapies, and radiopharmaceutical therapies (RPTs).