Theranostic Targeting of CUB Domain Containing Protein 1 (CDCP1) in Pancreatic Cancer
| Autor: | Alexander J. Martinko, Lydia H. Zhang, Kevin Leung, Eric A. Collisson, Anna Moroz, Sean D. Carlin, Ning Zhao, Kimberly S. Kirkwood, Yung-hua Wang, Michael J. Evans, Shion A. Lim, Zhuo Chen, Jie Zhuo, Junnian Wei, James A. Wells, Jeremy Sharib, Yangjie Huang, Youngho Seo |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Cancer Research Single Photon Emission Computed Tomography Computed Tomography Oncology and Carcinogenesis Antineoplastic Agents Article 03 medical and health sciences Mice Pancreatic Cancer 0302 clinical medicine Antineoplastic Agents Immunological Rare Diseases Antigens Neoplasm Pancreatic cancer Positron Emission Tomography Computed Tomography medicine Radioligand Animals Humans Tissue Distribution Oncology & Carcinogenesis Antigens Precision Medicine Cytotoxicity Pancreas Cancer biology business.industry medicine.disease CUB domain Xenograft Model Antitumor Assays Pancreatic Neoplasms 030104 developmental biology Immunological Oncology Ectodomain 030220 oncology & carcinogenesis CDCP1 biology.protein Cancer research Neoplasm Antibody business Digestive Diseases Cell Adhesion Molecules |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research, vol 26, iss 14 Clin Cancer Res |
| Popis: | Purpose: The recent emergence of radioligand therapies for cancer treatment has increased enthusiasm for developing new theranostic strategies coupling both imaging and cytotoxicity in the same entity. In this study, we evaluated whether CUB domain containing protein 1 (CDCP1), a single-pass transmembrane protein highly overexpressed in diverse human cancers, might be a target for cancer theranostics. Experimental Design: The ectodomain of CDCP1 was targeted using radiolabeled forms of 4A06, a potent and specific recombinant human antibody that we developed. Imaging and antitumor assessment studies were performed in animal models of pancreatic cancer, including two patient-derived xenograft models we developed for this study. For antitumor assessment studies, the endpoints were death due to tumor volume >3,000 mm3 or ≥20% loss in body weight. Specific tracer binding or antitumor effects were assessed with an unpaired, two-tailed Student t test and survival advantages were assessed with a log rank (Mantel–Cox) test. Differences at the 95% confidence level were interpreted to be significant. Results: 89Zr-4A06 detected a broad dynamic range of full length or cleaved CDCP1 expression on seven human pancreatic cancer tumors (n = 4/tumor). Treating mice with single or fractionated doses of 177Lu-4A06 significantly reduced pancreatic cancer tumor volume compared with mice receiving vehicle or unlabeled 4A06 (n = 8; P < 0.01). A single dose of 225Ac-4A06 also inhibited tumor growth, although the effect was less profound compared with 177Lu-4A06 (n = 8; P < 0.01). A significant survival advantage was imparted by 225Ac-4A06 (HR = 2.56; P < 0.05). Conclusions: These data establish that CDCP1 can be exploited for theranostics, a finding with widespread implications given its breadth of overexpression in cancer. |
| Databáze: | OpenAIRE |
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