Anti-CDCP1 immuno-conjugates for detection and inhibition of ovarian cancer

Harrington, Brittney S.; He, Yaowu; Khan, Tashbib; Puttick, Simon; Conroy, Paul J.; Kryza, Thomas; Cuda, Tahleesa; Sokolowski, Kamil A.; Tse, Brian Wan-Chi; Robbins, Katherine K.; Arachchige, Buddhika J.; Stehbens, Samantha J.; Pollock, Pamela M.; Reed, Sarah C.; Weroha, S. John; Haluska, Paul; Salomón, Carlos; Lourie, Rohan; Perrin, Lewis; Law, Ruby H. P.; Whisstock, James C.; Hooper, John D.

doi:10.7150/thno.30736

Cited by 17 publications

(33 citation statements)

References 65 publications

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“…To identify a cell line suitable for CDCP1-targeted radioligand molecular imaging, flow cytometry assessing cell surface expression of CDCP1 was performed on the three CRC lines HT29, SW480, and HCT116, with ovarian cancer OVMZ6 cells used as a negative control and prostate cancer PC3 cells as a positive control [ 25 , 33 ]. As shown in Figure 1(a) , cell surface levels of CDCP1 were the highest on HCT116 and SW480 cells, comparable to levels on prostate cancer PC3 cells, while levels were at least 50% lower on HT29 CRC cells.…”

Section: Resultsmentioning

confidence: 99%

“…At 50% confluence, adherent cells were nonenzymatically detached in PBS/EDTA (0.48 mM) and counted. Cells (2.5 × 10 5 ) were washed twice in PBS, blocked in PBS containing 2% FCS for 30 minutes, and stained with mouse anti-CDCP1 aminoterminal antibody 10D7 for 1 hour at 4°C [ 25 ]. Cells were then washed twice in PBS containing 2% FCS for 30 minutes at 4°C before incubation with an Alexa Fluor 488-conjugated goat anti-mouse secondary antibody at 4°C for 30 minutes (Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

“…CDCP1 is expressed as a full-length 135 kDa protein and can also undergo proteolytic cleavage generating a 70 kDa membrane-spanning carboxyl-terminal fragment and a 65 kDa aminoterminal fragment that is either shed from the cell surface or remains bound to CDCP1 on the plasma membrane [ 24 ]. Previous studies have demonstrated the utility of mouse monoclonal 10D7 antibody that binds to the CDCP1 amino terminal, for delivery of Zirconium-89 ( 89 Zr) for PET-CT-based detection, and cytotoxins for treatment of preclinical models of ovarian [ 25 ] and pancreatic [ 24 ] cancer. In CRC, elevated CDCP1 correlates with poorer patient outcome [ 3 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Preclinical Molecular PET-CT Imaging Targeting CDCP1 in Colorectal Cancer

Cuda

Kryza

et al. 2021

Contrast Media & Molecular Imaging

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Colorectal cancer (CRC) is the third most common malignancy in the world, with 22% of patients presenting with metastatic disease and a further 50% destined to develop metastasis. Molecular imaging uses antigen-specific ligands conjugated to radionuclides to detect and characterise primary cancer and metastases. Expression of the cell surface protein CDCP1 is increased in CRC, and here we sought to assess whether it is a suitable molecular imaging target for the detection of this cancer. CDCP1 expression was assessed in CRC cell lines and a patient-derived xenograft to identify models suitable for evaluation of radio-labelled 10D7, a CDCP1-targeted, high-affinity monoclonal antibody, for preclinical molecular imaging. Positron emission tomography-computed tomography was used to compare zirconium-89 (89Zr)-10D7 avidity to a nonspecific, isotype control 89Zr-labelled IgGκ1 antibody. The specificity of CDCP1-avidity was further confirmed using CDCP1 silencing and blocking models. Our data indicate high avidity and specificity for of 89Zr-10D7 in CDCP1 expressing tumors at. Significantly higher levels than normal organs and blood, with greatest tumor avidity observed at late imaging time points. Furthermore, relatively high avidity is detected in high CDCP1 expressing tumors, with reduced avidity where CDCP1 expression was knocked down or blocked. The study supports CDCP1 as a molecular imaging target for CRC in preclinical PET-CT models using the radioligand 89Zr-10D7.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Preclinical Molecular PET-CT Imaging Targeting CDCP1 in Colorectal Cancer

Cuda

Kryza

et al. 2021

Contrast Media & Molecular Imaging

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“…This included genes previously suspected to be associated with RCC survival, notably immune related biomarkers, namely RARRES1 ( 36 , 37 ), interleukin receptor IL20RB ( 38 , 39 ), immune activator CLEC3B ( 40 , 41 ) and tetraspanin TSPAN 7 ( 42 , 43 ), as well as several hypoxia-inducible factors target genes such as CDCP1 ( 44 ), FYN ( 45 ) and TRIB3 ( 46 ), of particular interest given the key role of oxygen and metabolism homeostasis in kidney cancer. Mounting evidence is suggesting the pro-tumorigenic signaling protein CDCP1 as a promising therapeutic target for multiple cancer types, including at the metastatic stage ( 47 ). TRIB3 is also being investigated as a cancer biomarker and therapeutic target, especially in the context of its stress adjusting action that links homeostasis, metabolic disease and cancer ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

Sexual dimorphism in cancer: insights from transcriptional signatures in kidney tissue and renal cell carcinoma

Laskar

Ecsedi

Abedi‐Ardekani

et al. 2021

Human Molecular Genetics

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Sexual dimorphism in cancer incidence and outcome is widespread. Understanding the underlying mechanisms is fundamental to improve cancer prevention and clinical management. Sex disparities are particularly striking in kidney cancer: across diverse populations, men consistently show unexplained two-fold increased incidence and worse prognosis. We have characterized genome-wide expression and regulatory networks of 609 renal tumors and 256 non-tumor renal tissues. Normal kidney displayed sex-specific transcriptional signatures, including higher expression of X-linked tumor suppressor genes in women. Sex-dependent genotype–phenotype associations unraveled women-specific immune regulation. Sex differences were markedly expanded in tumors, with male-biased expression of key genes implicated in metabolism, non-malignant diseases with male predominance, and carcinogenesis, including markers of tumor infiltrating leukocytes. Analysis of sex-dependent RCC progression and survival uncovered prognostic markers involved in immune response and oxygen homeostasis. In summary, human kidney tissues display remarkable sexual dimorphism at the molecular level. Sex-specific transcriptional signatures further shape renal cancer, with relevance for clinical management.

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“…The stain was removed after 20 min and plates scanned using an Odyssey Imaging System and associated V3.0 software (LI-COR Biosciences, Millennium Science, Mulgrave, Australia) at 700 nm wavelength. Images were processed in ImageJ software, and the colony area and staining intensity quantified for each well using the ColonyArea ImageJ plugin, as described [41,42].…”

Section: Colony Formation Assaymentioning

confidence: 99%

Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma

Khan

Kryza

et al. 2020

Cancers

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High stage and recurrent ovarian clear cell carcinoma (OCC) are associated with poor prognosis and resistance to chemotherapy. A distinguishing histological feature of OCC is abundant cytoplasmic stores of glucose, in the form of glycogen, that can be mobilized for cellular metabolism. Here, we report the effect on preclinical models of OCC of disrupting glycogen utilization using the glucose analogue 2-deoxy-D-glucose (2DG). At concentrations significantly lower than previously reported for other cancers, 2DG markedly improves the efficacy in vitro of carboplatin chemotherapy against chemo-sensitive TOV21G and chemo-resistant OVTOKO OCC cell lines, and this is accompanied by the depletion of glycogen. Of note, 2DG doses—of more than 10-fold lower than previously reported for other cancers—significantly improve the efficacy of carboplatin against cell line and patient-derived xenograft models in mice that mimic the chemo-responsiveness of OCC. These findings are encouraging, in that 2DG doses, which are substantially lower than previously reported to cause adverse events in cancer patients, can safely and significantly improve the efficacy of carboplatin against OCC. Our results thus justify clinical trials to evaluate whether low dose 2DG improves the efficacy of carboplatin in OCC patients.

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Anti-CDCP1 immuno-conjugates for detection and inhibition of ovarian cancer

Cited by 17 publications

References 65 publications

Preclinical Molecular PET-CT Imaging Targeting CDCP1 in Colorectal Cancer

Preclinical Molecular PET-CT Imaging Targeting CDCP1 in Colorectal Cancer

Sexual dimorphism in cancer: insights from transcriptional signatures in kidney tissue and renal cell carcinoma

Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma

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