Receptor CDCP1 Is a Potential Target for Personalized Imaging and Treatment of Poor Outcome HER2+, Triple-Negative, and Metastatic ER+/HER2- Breast Cancers

Gough, M; Kwah, KKX; Lee, CYJ; Khan, T; Tse, BWC; Ghosh, S; Sun, B; Sokolowski, KA; Wickramasuriya, L; Ferguson, K; Rogers, R; Goh, JB; Fletcher, NL; Houston, ZH; Thurecht, KJ; Bray, LJ; Liu, C; Pyke, C; Lim, E; Snell, CE; He, Y; Hooper, JD; Kryza, T

Author(s): Gough, M; Kwah, KKX; Lee, CYJ; Khan, T; Tse, BWC; Ghosh, S; Sun, B; Sokolowski, KA; Wickramasuriya, L; Ferguson, K; Rogers, R; Goh, JB; Fletcher, NL; Houston, ZH; Thurecht, KJ; Bray, LJ; Liu, C; Pyke, C; Lim, E; Snell, CE; He, Y; Hooper, JD; Kryza, T;
Details: Publication Year 2025-04-14,Volume 31,Issue #8,Page 1504-1519
Journal Title: Clinical Cancer Research
Publication Type: Research 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.
Publisher: American Association for Cancer Research
Keywords: Humans; Animals; Female; Mice; *Triple Negative Breast Neoplasms/drug; therapy/pathology/metabolism/genetics/diagnostic imaging; *Receptor, ErbB-2/metabolism/genetics; *Cell Adhesion Molecules/metabolism/antagonists & inhibitors/genetics; Receptors, Estrogen/metabolism/genetics; Xenograft Model Antitumor Assays; Cell Line, Tumor; Immunoconjugates/administration & dosage; Antigens, Neoplasm; *Neoplasm Proteins/metabolism/antagonists & inhibitors/genetics; Positron Emission Tomography Computed Tomography; Precision Medicine; Oligopeptides/administration & dosage; Maytansine/analogs & derivatives/administration & dosage; Ado-Trastuzumab Emtansine; *Antigens, CD/metabolism/genetics; Neoplasm Metastasis; Zirconium; Trastuzumab/administration & dosage
Department(s): Pathology
Publisher's Version: https://doi.org/10.1158/1078-0432.Ccr-24-2865
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-01-30 02:31:24

Last Modified: 2025-05-08 07:28:38