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Published on: October 30, 2013
Theranostic Targeting of CUB Domain-Containing Protein 1 (CDCP1) in Multiple Subtypes of Bladder Cancer
Shalini Chopra1, Kai Trepka2,3, Sasank Sakhamuri1
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California.
Purpose:
Despite recent approvals for checkpoint inhibitors and antibody-drug conjugates targeting NECTIN4 or TROP2, metastatic bladder cancer remains incurable and new treatment strategies are urgently needed. CUB domain-containing protein 1 (CDCP1) is a cell surface protein and promising drug target for many cancers. This study aimed to determine whether CDCP1 is expressed in bladder cancer and whether CDCP1 can be targeted for treatment with radiolabeled antibodies.
Experimental Design:
CDCP1 expression was evaluated in four bladder cancer datasets (n = 1,047 biopsies). A tissue microarray of primary bladder cancer biopsies was probed for CDCP1 by IHC. CDCP1 expression was evaluated in patient-derived xenografts and cell lysates by immunoblot, flow cytometry, and saturation binding assays. Tumor detection in mouse bladder cancer models was tested using 89Zr-labeled 4A06, a monoclonal antibody targeting the ectodomain of CDCP1. 177Lu-4A06 was applied to mice bearing UMUC3 or HT-1376 xenografts to evaluate antitumor effects (CDCP1 expression in UMUC3 is 10-fold higher than HT-1376).
Results:
CDCP1 was highest in the basal/squamous subtype, and CDCP1 was expressed in 53% of primary biopsies. CDCP1 was not correlated with pathologic or tumor stage, metastatic site, or NECTIN4 and TROP2 at the mRNA or protein level. CDCP1 ranged from 105 to 106 receptors per cell. Mechanism studies showed that RAS signaling induced CDCP1 expression. 89Zr-4A06 PET detected five human bladder cancer xenografts. 177Lu-4A06 inhibited the growth of UMUC3 and HT-1376 xenografts, models with high and moderate CDCP1 expression, respectively.
Conclusions:
These data establish that CDCP1 is expressed in bladder cancer, including TROP2 and NECTIN4-null disease, and suggest that bladder cancer can be treated with CDCP1-targeted radiotherapy.
Insights
CUB domain-containing protein 1 (CDCP1) is expressed in bladder cancer, offering a new target for treatment. Radiolabeled antibodies targeting CDCP1 demonstrated tumor detection and growth inhibition in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Radiochemistry
Background:
- Metastatic bladder cancer remains incurable despite advances in targeted therapies.
- CUB domain-containing protein 1 (CDCP1) is a cell surface protein implicated as a drug target in various cancers.
Purpose of the Study:
- To investigate CDCP1 expression in bladder cancer.
- To evaluate the therapeutic potential of CDCP1-targeted radiolabeled antibodies.
Main Methods:
- Analysis of CDCP1 expression in bladder cancer datasets and patient biopsies using IHC.
- Evaluation of CDCP1 in xenografts and cell lines via immunoblot, flow cytometry, and binding assays.
- Assessment of tumor detection using 89Zr-labeled anti-CDCP1 antibody (4A06) and therapeutic efficacy of 177Lu-labeled 4A06 in mouse models.
Main Results:
- CDCP1 is expressed in 53% of primary bladder cancer biopsies, particularly in the basal/squamous subtype.
- CDCP1 expression levels (10^5-10^6 receptors/cell) were independent of tumor stage or other targeted markers.
- 89Zr-4A06 PET successfully detected bladder cancer xenografts, and 177Lu-4A06 significantly inhibited tumor growth in preclinical models.
Conclusions:
- CDCP1 is a viable therapeutic target in bladder cancer, including cases negative for TROP2 and NECTIN4.
- CDCP1-targeted radiotherapy represents a promising new treatment strategy for bladder cancer.
