Glycoprotein mucin 13 expression as a theranostic target in colorectal cancer

PURPOSE: The high mortality associated with metastatic colorectal cancer (mCRC) illuminates an unmet need for innovative therapeutic modalities. Radiopharmaceutical therapy (RPT) offers a potent, molecular scale approach for managing and treating cancers with distant micrometastases. However, its clinical use in mCRC remains an unrealized opportunity. We have therefore identified the transmembrane glycoprotein mucin 13 (MUC13) as a promising antigen for developing a targeted RPT and have undertaken preclinical evaluation of its potential through utilizing a monoclonal antibody tool representative of a future class of translatable therapeutics. EXPERIMENTAL DESIGN: The immunoreactivity and transcriptome of CRC patients (n=72 primary, 100 liver metastasis) were characterized using annotated clinical datasets. Preclinical assessment of MUC13 as an RPT target for mCRC was then performed in mice using a monoclonal MUC13-targeted antibody "C14" labeled with either zirconium-89 (89Zr) for positron emission tomography (PET) measurement of mCRC-associated MUC13 density or terbium-161 (161Tb) for targeted RPT. RESULTS: Strong MUC13 immunoreactivity was observed in ~70% of mCRCs and inversely correlated with overall survival (P<0.01). MUC13 levels were visualized by PET and agreed with immunohistochemically determined antigen presence. Furthermore, MUC13-targeted RPT exhibited in vivo proof-of-concept efficacy and enhanced survival in preclinical CRC models. Resulting imaging, therapeutic, and pathological analyses elucidated relationships between target density, therapeutic outcome, and a potential genetic signature. CONCLUSIONS: MUC13-targeted RPT response was not only associated with radiopharmaceutical accumulation but also appeared to be balanced by DNA damage repair gene expression, suggesting a potential sensitivity signature that could complement a future clinical theranostic approach in MUC13-positive mCRC.