Insulin-Like Growth Factor Bioactivity, Stanniocalcin-2, Pregnancy-Associated Plasma Protein-A, and IGF-Binding Protein-4 in Pleural Fluid and Serum From Patients With Pulmonary Disease

Espelund, Ulrick; Bjerre, Mette; Hjortebjerg, Rikke; Rasmussen, Torben Riis; Lundby, Anders; Hoeflich, Andreas; Folkersen, Birgitte Holst; Oxvig, Claus; Frystyk, Jan

doi:10.1210/jc.2017-00033

Cited by 32 publications

(20 citation statements)

References 36 publications

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“…In 2013, a whole-exome sequencing study of lung adenocarcinoma patients identified PAPPA2 gene mutations that were associated with prolonged survival times ( 40 ). In 2017, the present authors investigated PAPP-A, PAPP-A2 and IGF activity in pleural fluid collected at baseline from a limited number of patients with lung cancer ( n = 24) ( 18 ). The study showed that the distribution of IGF system proteins in pleural effusions was substantially different from that of the circulating IGF system.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, PAPP-A causes a release of bioactive IGF in close proximity to the IGF-IR. Shifts in PAPP-A levels have been suggested to modify the relationship between bound and free IGF in various neoplasms ( 8 , 18 – 20 ). In patients with lung cancer, serum PAPP-A levels have been shown to be elevated ( 19 ), and down-regulation of PAPP-A expression decreases lung cancer progression in vivo ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

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Pregnancy-Associated Plasma Protein-A2 Is Associated With Mortality in Patients With Lung Cancer

et al. 2020

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Pregnancy-associated plasma protein-A (PAPP-A) and its homolog PAPP-A2 are enzymes that modulate the availability and mitogenic activity of insulin-like growth factor-I (IGF-I). PAPP-A has been implicated in numerous cancers but reports on PAPP-A2 in malignancy are non-existent. In a prospective observational study of 689 patients under suspicion of lung cancer, we examined levels of PAPP-A and PAPP-A2 and their relationship with mortality. Serum PAPP-A and PAPP-A2 concentrations were determined in pre-diagnostic blood samples using ELISA, and immunohistochemical staining of PAPP-A and PAPP-A2 was performed in malignant tissue from five operable patients. A total of 144 patients were diagnosed with lung cancer, whereas the diagnosis was rejected in 545 subjects, who served as a control group. PAPP-A2 concentrations were higher in patients with lung cancer [median (IQR): 0.33 (0.21–0.56) ng/mL] than in controls [0.27 (0.17–0.39) ng/mL], p < 0.001, whereas PAPP-A levels did not differ. Presence of PAPP-A and PAPP-A2 were confirmed in tumor specimens, and staining occurred in a heterogeneous pattern. Patients were observed for a median (range) of 7 (6; 8) years, during which 114 patients (79.2%) died. Patient mortality differed according to PAPP-A2 tertile ( p < 0.001). PAPP-A2 was associated with mortality with an unadjusted hazard ratio (95% CI) per doubling in protein concentration of 1.30 (1.12; 1.53), p = 0.001. In a multivariable model adjusted for age, sex, and BMI, PAPP-A2 remained predictive of the endpoint with a hazard ratio per doubling in protein concentration of 1.25 (1.05; 1.48), p = 0.013. Collectively, PAPP-A2, but not PAPP-A, is elevated in patients with lung cancer and associated with mortality. This novel role of PAPP-A2 in cancer warrants further functional studies as well as validation in external cohorts.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pregnancy-Associated Plasma Protein-A2 Is Associated With Mortality in Patients With Lung Cancer

et al. 2020

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“…Indeed, we have recent data indicating that PAPP‐A only affects IGFBP‐2 marginally. In pleural effusions, where PAPP‐A is close to 50‐fold elevated as compared to serum, the degradation of IGFBP‐2 remains similar to that in serum and in serum from lung cancer patients the major part of IGFBP‐2 circulates in its free form (data in preparation). On the basis of our recent and present data, we speculate that in vivo, IGFBP‐2 is primarily unoccupied and hence not only protected against PAPP‐A degradation but also able to suppress PTEN .…”

Section: Discussionmentioning

confidence: 94%

Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort study

et al. 2018

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Measurement of circulating insulin‐like growth factors (IGFs), in particular IGF‐binding protein (IGFBP)‐2, at the time of diagnosis, is independently prognostic in many cancers, but its clinical performance against other routinely determined prognosticators has not been examined. We measured IGF‐I, IGF‐II, pro‐IGF‐II, IGF bioactivity, IGFBP‐2, ‐3, and pregnancy‐associated plasma protein A (PAPP‐A), an IGFBP regulator, in baseline samples of 301 women with breast cancer treated on four protocols (Odense, Denmark: 1993–1998). We evaluated performance characteristics (expressed as area under the curve, AUC) using Cox regression models to derive hazard ratios (HR) with 95% confidence intervals (CIs) for 10‐year recurrence‐free survival (RFS) and overall survival (OS), and compared those against the clinically used Nottingham Prognostic Index (NPI). We measured the same biomarkers in 531 noncancer individuals to assess multidimensional relationships (MDR), and evaluated additional prognostic models using survival artificial neural network (SANN) and survival support vector machines (SSVM), as these enhance capture of MDRs. For RFS, increasing concentrations of circulating IGFBP‐2 and PAPP‐A were independently prognostic [HR biomarker doubling: 1.474 (95% CIs: 1.160, 1.875, P = 0.002) and 1.952 (95% CIs: 1.364, 2.792, P < 0.001), respectively]. The AUCRFS for NPI was 0.626 (Cox model), improving to 0.694 (P = 0.012) with the addition of IGFBP‐2 plus PAPP‐A. Derived AUCRFS using SANN and SSVM did not perform superiorly. Similar patterns were observed for OS. These findings illustrate an important principle in biomarker qualification—measured circulating biomarkers may demonstrate independent prognostication, but this does not necessarily translate into substantial improvement in clinical performance.

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“…The KIRA assay was used to assess residual ligand bioactivity in the circulation of IGF-TRAP-treated mice and performed as described in detail elsewhere 19 , 29 including recent modifications 30 . In brief, HEK293 cells overexpressing IGF-1R were cultured in complete DMEM medium (containing 1% Penicillin/Streptomycin, 0.5 mg/ml G418, 0.25 mg/ml Hygromycin, 10% FCS).…”

Section: Methodsmentioning

confidence: 99%

Enhanced anti-metastatic bioactivity of an IGF-TRAP re-engineered to improve physicochemical properties

Vaniotis

Moffett

Sulea

et al. 2018

Sci Rep

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The insulin-like growth factor (IGF) axis has been implicated in the progression of malignant disease and identified as a clinically important therapeutic target. Several IGF-1 receptor (IGF-1R) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signalling. We previously reported on the production of a soluble fusion protein consisting of the extracellular domain of human IGF-1R fused to the Fc portion of human IgG1 (first generation IGF-TRAP) that bound human IGF-1 and IGF-2 with a 3 log higher affinity than insulin. We showed that the IGF-TRAP had potent anti-cancer activity in several pre-clinical models of aggressive carcinomas. Here we report on the re-engineering of the IGF-TRAP with the aim of improving physicochemical properties and suitability for clinical applications. We show that cysteine-serine substitutions in the Fc hinge region of IGF-TRAP eliminated high-molecular-weight oligomerized species, while a further addition of a flexible linker, not only improved the pharmacokinetic profile, but also enhanced the therapeutic profile of the IGF-TRAP, as evaluated in an experimental colon carcinoma metastasis model. Dose-response profiles of the modified IGF-TRAPs correlated with their bio-availability profiles, as measured by the IGF kinase-receptor-activation (KIRA) assay, providing a novel, surrogate biomarker for drug efficacy. This study provides a compelling example of structure-based re-engineering of Fc-fusion-based biologics for better manufacturability that also significantly improved pharmacological parameters. It identifies the re-engineered IGF-TRAP as a potent anti-cancer therapeutic.

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Insulin-Like Growth Factor Bioactivity, Stanniocalcin-2, Pregnancy-Associated Plasma Protein-A, and IGF-Binding Protein-4 in Pleural Fluid and Serum From Patients With Pulmonary Disease

Cited by 32 publications

References 36 publications

Pregnancy-Associated Plasma Protein-A2 Is Associated With Mortality in Patients With Lung Cancer

Pregnancy-Associated Plasma Protein-A2 Is Associated With Mortality in Patients With Lung Cancer

Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort study

Enhanced anti-metastatic bioactivity of an IGF-TRAP re-engineered to improve physicochemical properties

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