Receptor CDCP1 Is a Potential Target for Personalized Imaging and Treatment of Poor Outcome HER2+, Triple-Negative, and Metastatic ER+/HER2− Breast Cancers
In this study by Gough et al., PET/CT imaging with the β-CUBE (PET) and X-CUBE (CT) systems was used to detect CDCP1-expressing primary and metastatic breast tumors in mice using the radiolabeled antibody 89Zr-ch10D7. Following confirmation of strong tumor targeting, the therapeutic efficacy of the cytotoxin-conjugated antibody ch10D7-MMAE was evaluated, showing reduced tumor burden and improved survival in mice.
Research question
CDCP1 is a receptor commonly overexpressed in aggressive breast cancer subtypes (including triple-negative breast cancer (TNBC)) and represents a promising target for both therapeutic intervention and non-invasive imaging. This study explores the potential of a radiolabeled anti-CDCP1 antibody (89Zr-ch10D7) to detect CDCP1-expressing tumors with in vivo PET/CT imaging. Further, it was investigated if PET/CT could effectively visualize both primary and metastatic lesions in breast cancer models, helping to identify patients who might benefit from CDCP1-targeted therapies.
After confirming strong accumulation of ch10D7 in primary TNBC xenografts via PET-CT, the study tested the therapeutic effect of the cytotoxin-conjugated antibody ch10D7-MMAE on tumor growth and survival in mice using two different orthotopic breast cancer models.
Experiment
PET and CT imaging were performed on anaesthetized female NSG mice carrying mammary fat pad (orthotopic) or metastatic breast cancer xenografts using the β-CUBE (PET) and X-CUBE (CT). PET-CT imaging was performed at different time points, namely after 24, 48 and 72 h, and for some tests after 120 h after 89Zr-ch10D7 injection.
For PET imaging, mice were injected intravenously with 89Zr-ch10D7 (~2.0 MBq; 0.1 ml; 20 minutes acquisition), and the CT parameters used were 50 kV, 75 µA, 480 exposures at 85 ms each, with continuous helical rotation.
Results
PET-CT scans indicated that within 24 h, 89Zr-ch10D7 accumulated strongly and selectively in all TNBC xenografts, with signal extended until the 48 and 72 h timepoints. In metastatic TNBC models, PET-CT imaging of mice at 24, 48 and 120 h after administration of 89Zr-ch10D7 showed sustained signal in lungs identifying CDCP1-expressing tumors.
Treatments with the therapeutic antibody ch10D7-MMAE significantly reduced tumor burden, in contrast to control conditions using PBS or carboplatin, which showed no effective tumor control.
In conclusion, ch10D7 showed strong accumulation in orthotopic TNBC models and effectively delivered the cytotoxic payload MMAE, leading to a significant reduction in tumor burden and improved survival in TNBC xenograft mice.
Molecular imaging with PET-CT has the potential to enhance patient selection for receptor-targeted therapies by using high-affinity theranostic agents to visualize both the location and intensity of target expression, enabling more precise and personalized treatment with therapeutic radionuclides or antibody-drug conjugates.
