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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.

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.

CDCP1 mRNA is not correlated NECTIN4 or TROP2 mRNA, related to Figure 2C. Spearman correlation analyses were performed between CDCP1 and NECTIN4 or TROP2 for the Seiler, Sjodahl 2017, and Sjodahl 2012 datasets, with p values and correlation coefficients shown. Points are colored by consensus subtype as in Figure 1.

CDCP1 mRNA expression by site of biopsy, from the IMvigor210 dataset. p = 0.075 by Kruskal-Wallis test, n=348 samples

CDCP1 mRNA expression is not associated with overall survival. Kaplan–Meier survival analyses were performed on quartiles of CDCP1 mRNA expression with overall survival as the endpoint. p > 0.05 in both public datasets for which overall survival data were available.

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.

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.

CDCP1 mRNA expression by pathologic stage in the TCGA dataset. p=0.72 by Kruskal-Wallis test.

CDCP1 mRNA is overexpressed in basal/squamous subtypes of bladder cancer, related to Figure 1A-D. Pairwise comparisons of CDCP1 expression between bladder cancer consensus subtypes using the Wilcoxon rank-sum test across four different datasets are shown.

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.

CDCP1 protein expression by clinical stage using the tissue microarray. p=0.32 by Kruskal-Wallis test.

CDCP1 mRNA expression by clinical stage in the Seiler dataset. p=0.12 by Kruskal-Wallis test.

CDCP1 mRNA expression in locally-advanced vs metastatic patients, from the IMvigor210 dataset. p=0.55 by Wilcoxon test, n=316 patients.

Supplementary Table from CUB Domain-Containing Protein 1 (CDCP1) Is a Target for Radioligand Therapy in Castration-Resistant Prostate Cancer, including PSMA Null Disease

Supplementary Figure from CUB Domain-Containing Protein 1 (CDCP1) Is a Target for Radioligand Therapy in Castration-Resistant Prostate Cancer, including PSMA Null Disease

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.

Smart Home devices are IoT (Internet of Things) enabled devices used to enhance wellbeing within the home environment. Around 63% of IoT devices are Smart Home devices. Although IoT devices have been available for a while, recent studies show that acceptance of Smart Home devices is limited to innovators and early adopters. Interestingly it has been observed that some categories of Smart Home devices are more popular suggesting that there is variance in acceptance of IoT devices. This research investigates the differences in consumer acceptance of various Smart Home device categories. Smart Home devices were categorised into three categories: 1) Technology and Entertainment; 2) domestic appliances; 3) housekeeping devices. The research focuses on the investigation of the reasons and factors influencing behaviour intention and use behaviour for each of the defined Smart Home device categories. An adapted version of the Unified Theory of Acceptance and Use of Technology (UTAUT2) model was used to study technology acceptance. The PLS-SEM technique, facilitated by SmartPLS 3.0 software, was used to perform the analysis. Our study confirms that behavioural intention to adopt and use Smart Home devices, and the factors driving adoption, varies between Smart Home IoT categories. Accordingly, it is vital to consider device type distinctively when considering Smart Home IoT adoption and usage.

Demonstrating target engagement in vivo is an important milestone in drug development, both to establish on target, on tissue interactions but also to identify potentially undesirable off tissue binding. The glucocorticoid receptor (GR) is a long-studied yet vexing drug target that has recently re-emerged as a potential druggable driver of many solid tumor types including breast and prostate cancer, and several antagonists are currently in early phase clinical trials. Since GR is also ubiquitously expressed in normal tissues, understanding antagonist/GR interactions in normal tissues and tumor is crucial to defining a therapeutic index. Herein, we demonstrate that the GR radioligand

The antimicrobial peptide fragment GF-17 was synthesized in-house and conjugated with DOTA and measured molecular mass of DOTA-GF-17 conjugate was 2489 Da. The peptide conjugate was purified and labeled with [68Ga]. The best radiolabeling efficiency (95.0%) of [68Ga]DOTA-GF-17 was achieved at pH 4 with peptide conjugate amount of 20.0 nmol with 30 min of heating at 95 °C. The product remained stable for up to 3 h. The plasma protein binding and lipophilicity for [68Ga]DOTA-GF-17 were 80.98% and −3.12 respectively. The uptake studies with [68Ga]DOTA- GF-17 in S.aureus and P.aeruginosa bacterial strains demonstrated binding of 69.08% and 43.69% respectively. The animal bio-distribution and PET imaging studies were in agreement showing similar pattern for organs’ tracer distribution and renal excretion. The tracer had rapid blood clearance and uptake in bone marrow and muscles was very low. The highest uptake of [68Ga]DOTA-GF-17 was observed at 45 min and 120 min in S.aureus and P.aeruginosa infections respectively. [68Ga]DOTA-GF-17 could be a promising PET tracer and holds a great scope for taking the product further to perform extensive PET studies in animal infection (using gram negative/positive strains) models to prove the diagnostic utility of this novel PET tracer for futuristic clinical applications.

The antimicrobial peptide fragment GF-17 was synthesized in-house and conjugated with DOTA and measured molecular mass of DOTA-GF-17 conjugate was 2489 Da. The peptide conjugate was purified and labeled with [

To evaluate the diagnostic utility of a single vial ready to label with [99m]Tc kit preparation of DTPA-bis-methionine (DTPA-bis-MET) for the detection of primary breast cancer.The conjugate (DTPA-bis-MET) was synthesized by covalently conjugating two molecules of methionine to DTPA and formulated as a single vial ready to label with [99m]Tc lyophilized kit preparations. Thirty female patients (mean age=47.5±11.8 years; range=21-69 years) with radiological/clinical evidence of having primary breast carcinoma were subjected to [99m]Tc-methionine scintigraphy. The whole body (anterior and posterior) imaging was performed on all the patients at 5 minutes, 10 minutes, 1 hour, 2 hours, and 4 hours following an intravenous administration of 555-740 MBq radioactivity of [99m]Tc-methionine. In addition, scintimammography (static images; 256×256 matrix) at 1, 2, and 4 hours was also performed on all the patients.The resultant radiolabel, that is, [99m]Tc-DTPA-bis-MET, yielded high radiolabeling efficiency (97.0%), radiochemical purity (166-296 MBq/μmol), and shelf life (3 months). The radiotracer primarily gets excreted through the kidneys and localizes in the breast cancer lesions with high target-to-nontarget ratios. The mean±SD ratios on the scan-positive lesions acquired at 1, 2, and 4 hours postinjection were 3.6±0.48, 3.10±0.24, and 2.5±0.4, respectively. [99m]Tc-methionine scintimammography demonstrated an excellent sensitivity and positive predictive value of 96.0% each for the detection of primary breast cancer.Ready to label single vial kit formulations of DTPA-bis-MET can be easily synthesized as in-house production and conveniently used for the scintigraphic detection of breast cancer and other methionine-dependent tumors expressing the L-type amino acid transporter-1 receptor. The imaging technique thus could be a potential substitute for the conventional single-photon emission computed tomography (SPECT)-based tumor imaging agents, especially for tracers with nonspecific mitochondrial uptake. However, the diagnostic efficacy of [99m]Tc-methionine needs to be evaluated in a large cohort of patients through further multicentric trials.