CUB Domain-Containing Protein 1 (CDCP1) Is a Target for Radioligand Therapy in Castration-Resistant Prostate Cancer, including PSMA Null Disease.
Animals
Antigens, Neoplasm
/ genetics
Cell Adhesion Molecules
Dipeptides
/ adverse effects
Heterocyclic Compounds, 1-Ring
Humans
Male
Mice
Prostate-Specific Antigen
Prostatic Neoplasms, Castration-Resistant
/ drug therapy
Radioisotopes
/ therapeutic use
Radiopharmaceuticals
/ therapeutic use
Treatment Outcome
Zirconium
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 07 2022
15 07 2022
Historique:
received:
01
11
2021
revised:
07
03
2022
accepted:
17
05
2022
pubmed:
24
5
2022
medline:
19
7
2022
entrez:
23
5
2022
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 35604681
pii: 699115
doi: 10.1158/1078-0432.CCR-21-3858
pmc: PMC9288514
mid: NIHMS1811588
doi:
Substances chimiques
Antigens, Neoplasm
0
CDCP1 protein, human
0
Cell Adhesion Molecules
0
Dipeptides
0
Heterocyclic Compounds, 1-Ring
0
Radioisotopes
0
Radiopharmaceuticals
0
Zirconium
C6V6S92N3C
Prostate-Specific Antigen
EC 3.4.21.77
Zirconium-89
NTM296JU95
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3066-3075Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM097316
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM141323
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR023051
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA258297
Pays : United States
Organisme : NCI NIH HHS
ID : P41 CA196276
Pays : United States
Organisme : NIBIB NIH HHS
ID : R01 EB025207
Pays : United States
Organisme : NIH HHS
ID : S10 OD012301
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA191018
Pays : United States
Informations de copyright
©2022 American Association for Cancer Research.
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