Purpose:
With the improvement in overall survival with 177Lu-PSMA 617, radioligand therapy (RLT) is now a viable option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, responses are variable, in part due to low PSMA expression in 30% of patients. Herein, we evaluated whether the cell surface protein CUB domain-containing protein 1 (CDCP1) can be exploited to treat mCRPC with RLT, including in PSMA-low subsets.
Experimental Design:
CDCP1 levels were evaluated using RNA sequencing from 119 mCRPC biopsies. CDCP1 levels were assessed in 17 post–enzalutamide- or abiraterone-treated mCRPC biopsies, 12 patient-derived xenografts (PDX), and prostate cancer cell lines. 4A06, a recombinant human antibody that targets the CDCP1 ectodomain, was labeled with Zr-89 or Lu-177 and tested in tumor-bearing mice.
Results:
CDCP1 expression was observed in 90% of mCRPC biopsies, including small-cell neuroendocrine (SCNC) and adenocarcinomas with low FOLH1 (PSMA) levels. Fifteen of 17 evaluable mCRPC biopsies (85%) demonstrated membranous CDCP1 expression, and 4 of 17 (23%) had higher CDCP1 H-scores compared with PSMA. CDCP1 was expressed in 10 of 12 PDX samples. Bmax values of approximately 22,000, 6,200, and 2,800 fmol/mg were calculated for PC3, DU145, and C4–2B human prostate cancer cells, respectively. 89Zr-4A06 PET detected six human prostate cancer xenografts, including PSMA-low tumors. 177Lu-4A06 significantly suppressed growth of DU145 and C4–2B xenografts.
Conclusions:
The data provide the first evidence supporting CDCP1-directed RLT to treat mCRPC. Expanded studies are warranted to determine whether CDCP1 is a viable drug target for patients with mCPRC.
Purpose: Despite recent approvals for checkpoint inhibitors and antibody drug conjugates targeting NECTIN4 or TROP2, metastatic bladder cancer (BC) 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 BC and whether CDCP1 can be targeted for treatment with radiolabeled antibodies. Experimental Design: CDCP1 expression was evaluated in four BC datasets (n = 1,047 biopsies). A tissue microarray of primary BC biopsies was probed for CDCP1 by immunohistochemistry. CDCP1 expression was evaluated in patient derived xenografts and cell lysates. Tumor detection in mouse BC models was tested using 89Zr-labeled 4A06, a monoclonal antibody targeting the ectodomain of CDCP1. 177Lu-4A06 was applied to mice bearing UMUC3 or HT1376 xenografts to evaluate antitumor effects (CDCP1 expression in UMUC3 is 10 fold higher than HT1376). 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 - 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 HT1376 xenografts. Conclusions: These data establish that CDCP1 is expressed in BC, including TROP2 and NECTIN4-null disease, and suggest that BC can be treated with CDCP1-targeted radiotherapy.
Supplementary Figure from CUB Domain-Containing Protein 1 (CDCP1) Is a Target for Radioligand Therapy in Castration-Resistant Prostate Cancer, including PSMA Null Disease
<p>A summary of the data from saturation binding assays used to calculate Bmax and receptor number per cell for bladder cancer cell lines. The data are representative of two independent assays. Data are reported as mean ± standard deviation.</p>
<p>A plot showing the mean tumor volume for the vehicle and treated arms from the antitumor assessment study in mice bearing UMUC3 xenografts. The differences in mean between treatment arms was found to be significant (P < 0.001) using an unpaired, two tailed t test by day 20. Data are reported as mean ± standard deviation.</p>
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