受体CDCP1是预后不良的HER2阳性、三阴性和转移性ER阳性/HER2阴性乳腺癌个性化成像和治疗的潜在靶点。
Receptor CDCP1 Is a Potential Target for Personalized Imaging and Treatment of Poor Outcome HER2+, Triple-Negative, and Metastatic ER+/HER2- Breast Cancers.
作者信息
Gough Madeline, Kwah Kayden K X, Khan Tashbib, Ghosh Saikat, Sun Biao, Lee Catherine Y J, Sokolowski Kamil A, Tse Brian W C, Wickramasuriya Lashith, Ferguson Kaltin, Rogers Rebecca, Goh Justin B, Fletcher Nicholas L, Houston Zachary H, Thurecht Kristofer J, Bray Laura J, Liu Cheng, Pyke Christopher, Lim Elgene, Snell Cameron E, He Yaowu, Hooper John D, Kryza Thomas
机构信息
Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Australia.
Mater Health Services, South Brisbane, Australia.
出版信息
Clin Cancer Res. 2025 Apr 14;31(8):1504-1519. doi: 10.1158/1078-0432.CCR-24-2865.
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.
目的
评估含受体CUB结构域蛋白1（CDCP1）作为乳腺癌检测和治疗靶点的可能性。
实验设计
采用免疫组织化学方法评估423例患者肿瘤组织中CDCP1的表达情况[119例三阴性乳腺癌（TNBC）；75例HER2阳性；229例雌激素受体阳性/HER2阴性，包括228例原发性肿瘤、229例淋巴结转移瘤和47例远处转移瘤]。对由人/鼠嵌合抗体ch10D7和微管破坏剂单甲基澳瑞他汀E（MMAE）组成的靶向CDCP1的抗体药物偶联物（ADC）在体外诱导的细胞毒性进行定量分析，包括与靶向HER的ADC曲妥珠单抗-美坦新（T-DM1）联合使用的情况。使用锆-89标记的ch10D7通过PET-CT成像检测小鼠体内表达CDCP1的原发性和转移性异种移植瘤。在细胞系和患者来源的异种移植小鼠模型中，定量分析ch10D7-MMAE对体内肿瘤负荷和生存的影响，包括与T-DM1联合使用的情况。
结果
CDCP1主要表达于70%的TNBC、80%的HER2阳性肿瘤的恶性细胞表面，在雌激素受体阳性/HER2阴性肿瘤中，其表达从原发性肿瘤中的44.9%增加到淋巴结转移瘤中的56.4%，在远处转移瘤中增加到74.3%。用锆-89标记的ch10D7进行PET-CT成像可有效检测小鼠体内表达CDCP1的原发性和转移性TNBC。ADC ch10D7-MMAE在体外可杀死表达CDCP1的细胞，并可控制小鼠体内原发性和转移性TNBC异种移植瘤的生长，与化疗相比具有显著的生存优势。在体内，它与T-DM1相比具有优势，并且ch10D7-MMAE与T-DM1联合使用显示出最强的疗效，与T-DM1或ch10D7相比，可显著降低CDCP1阳性/HER2阳性异种移植瘤的肿瘤负荷并延长小鼠生存期。
结论
针对CDCP1的分子成像有潜力识别侵袭性乳腺癌，以便进行针对CDCP1的治疗。
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