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

IF 10.2 1区医学 Q1 ONCOLOGY Clinical Cancer Research Pub Date : 2025-04-14 DOI:10.1158/1078-0432.CCR-24-2865

Madeline Gough, Kayden K X Kwah, Tashbib Khan, Saikat Ghosh, Biao Sun, Catherine Y J Lee, Kamil A Sokolowski, Brian W C Tse, Lashith Wickramasuriya, Kaltin Ferguson, Rebecca Rogers, Justin B Goh, Nicholas L Fletcher, Zachary H Houston, Kristofer J Thurecht, Laura J Bray, Cheng Liu, Christopher Pyke, Elgene Lim, Cameron E Snell, Yaowu He, John D Hooper, Thomas Kryza

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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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受体CDCP1是个性化成像和治疗预后不良的HER2+、三阴性和转移性ER+/HER2-乳腺癌的潜在靶点。

目的：探讨CDCP1受体cub结构域蛋白1 （Receptor CUB-domain containing- protein 1, CDCP1）作为乳腺癌检测和治疗的靶点。实验设计：采用免疫组化方法对423例患者(119例三阴性乳腺癌（TNBC）；75 HER2 +;229例ER+/HER2-包括228例原发肿瘤，229例淋巴结和47例远处转移)。定量了一种靶向cdcp1的抗体-药物偶联物（ADC）（由人/小鼠嵌合抗体ch10D7和微管干扰物monomethyl auristatin E （MMAE）组成）体外诱导的细胞毒性，包括与靶向her2的ADC T-DM1联合诱导的细胞毒性。用89Zr-ch10D7 （89Zr-ch10D7）标记的PET-CT成像检测小鼠表达cdcp1的原发和转移异种移植物。在细胞系和患者来源的异种移植小鼠模型中量化了ch10D7-MMAE对肿瘤负荷和体内生存的影响，包括与T-DM1联合使用。结果：CDCP1主要表达于70%的tnbc和80%的HER2+肿瘤的恶性细胞表面，并且在ER+/HER2-肿瘤中从原发肿瘤的44.9%增加到淋巴结转移的56.4%和远处转移的74.3%。用89Zr-ch10D7进行PET-CT成像，可有效检测小鼠原发性和转移性表达cdcp1的tnbc。ADC ch10D7-MMAE在体外杀死表达cdcp1的细胞，并控制小鼠原发性和转移性TNBC异种移植物，比化疗具有显著的生存优势。与T-DM1相比，ch10D7- mmae联合T-DM1的疗效最为显著，与T-DM1或ch10D7相比，ch10D7- mmae联合T-DM1可显著降低CDCP1+/HER2+异种移植物的肿瘤负荷，延长小鼠生存期。结论：cdcp1定向分子成像具有鉴别侵袭性乳腺癌的潜力，可用于cdcp1靶向治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical Cancer Research 医学-肿瘤学

CiteScore

20.10

自引率

1.70%

发文量

1207

审稿时长

2.1 months

期刊介绍： Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.