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Article Abstract
Purpose: Receptor CUB domain-containing protein 1 (CDCP1) was evaluated as a target for detection and treatment of breast cancer.
Experimental Design: CDCP1 expression was assessed immunohistochemically in tumors from 423 patients [119 triple-negative breast cancer (TNBC); 75 HER2+; and 229 ER+/HER2-, including 228 primary tumors and 229 lymph node and 47 distant metastases). Cell cytotoxicity induced in vitro by a CDCP1-targeting antibody-drug conjugate (ADC), consisting of the human/mouse chimeric antibody ch10D7 and the microtubule disruptor monomethyl auristatin E (MMAE), was quantified, including in combination with HER-targeting ADC trastuzumab emtansine (T-DM1). Detection of CDCP1-expressing primary and metastatic xenografts in mice was examined by PET-CT imaging using zirconium-89-labeled ch10D7. The impact of ch10D7-MMAE on tumor burden and survival in vivo, including in combination with T-DM1, was quantified in cell line and patient-derived xenograft mouse models.
Results: CDCP1 is expressed predominantly on the surface of malignant cells of 70% of TNBC, 80% of HER2+ tumors, and increases in ER+/HER2- tumors from 44.9% in primary tumors to 56.4% in lymph node metastases and 74.3% in distant metastases. PET-CT imaging with zirconium-89-labeled ch10D7 is effective for the detection of primary and metastatic CDCP1-expressing TNBC in mice. ADC ch10D7-MMAE kills CDCP1-expressing cells in vitro and controls primary and metastatic TNBC xenografts in mice, conferring significant survival advantages over chemotherapy. It compares favorably to T-DM1 in vivo, and ch10D7-MMAE combined with T-DM1 showed the most potent efficacy, markedly reducing tumor burden of CDCP1+/HER2+ xenografts and prolonging mouse survival, compared with T-DM1 or ch10D7.
Conclusions: CDCP1-directed molecular imaging has the potential to identify aggressive breast cancers for CDCP1-targeted treatment.
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| http://dx.doi.org/10.1158/1078-0432.CCR-24-2865 | DOI Listing |
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