A Phase I Pharmacokinetic and Pharmacodynamic Study of Dalotuzumab (MK-0646), an Anti-Insulin-like Growth Factor-1 Receptor Monoclonal Antibody, in Patients with Advanced Solid Tumors

Atzori, Francesco; Tabernero, Josep; Cervantes, Andrés; Prudkin, Ludmila; Andreu, Jordi; Rodríguez-Braun, Edith; Domingo, Amparo Soler; Guijarro, Jorge; Gámez, Cristina; Rodón, Jordi; Cosimo, Serena Di; Brown, Holly; Clark, Jason; Hardwick, James S.; Beckman, Robert A.; Hanley, William D.; Hsu, Karl; Calvo, Emiliano; Roselló, Susana; Langdon, Ronald B.; Baselga, José

doi:10.1158/1078-0432.ccr-10-3336

Cited by 110 publications

(80 citation statements)

References 35 publications

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“…Although several studies demonstrated the clinical efficacy of IGF-1R inhibitor dalotuzumab in IGF-1R targeted therapies, little to no activity in vitro has been documented so far (25,26). In this study, exposure of ES cells to dalotuzumab showed a flow ratedependent drug response in flow perfusion bioreactors, with greater drug efficacy at higher flow rates.…”

Section: Discussionmentioning

confidence: 99%

Flow perfusion effects on three-dimensional culture and drug sensitivity of Ewing sarcoma

Santoro

Lamhamedi-Cherradi

Menegaz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

104

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Three-dimensional tumor models accurately describe different aspects of the tumor microenvironment and are readily available for mechanistic studies of tumor biology and for drug screening. Nevertheless, these systems often overlook biomechanical stimulation, another fundamental driver of tumor progression. To address this issue, we cultured Ewing sarcoma (ES) cells on electrospun poly(e-caprolactone) 3D scaffolds within a flow perfusion bioreactor. Flow-derived shear stress provided a physiologically relevant mechanical stimulation that significantly promoted insulin-like growth factor-1 (IGF1) production and elicited a superadditive release in the presence of exogenous IGF1. This finding is particularly relevant, given the central role of the IGF1/IGF-1 receptor (IGF-1R) pathway in ES tumorigenesis and as a promising clinical target. Additionally, flow perfusion enhanced in a rate-dependent manner the sensitivity of ES cells to IGF-1R inhibitor dalotuzumab (MK-0646) and showed shear stress-dependent resistance to the IGF-1R blockade. This study demonstrates shear stressdependent ES cell sensitivity to dalotuzumab, highlighting the importance of biomechanical stimulation on ES-acquired drug resistance to IGF-1R inhibition. Furthermore, flow perfusion increased nutrient supply throughout the scaffold, enriching ES culture over static conditions. Our use of a tissue-engineered model, rather than human tumors or xenografts, enabled precise control of the forces experienced by ES cells, and therefore provided at least one explanation for the remarkable antineoplastic effects observed by some ES tumor patients from IGF-1R targeted therapies, in contrast to the lackluster effect observed in cells grown in conventional monolayer culture. T he ability to treat cancer patients is critically dependent upon a robust drug discovery pipeline and an efficient method to select the most promising drug candidates for clinical trial advancement. Preclinical drug screening typically relies on the use of 2D culture systems, which are reproducible, fast, and inexpensive. Nevertheless, tumor phenotype is dictated by its interaction with the surrounding 3D microenvironment (1). The inability of 2D systems to mimic this key element has generally resulted in preclinical findings that overstate drug activity when subsequently tested in human clinical trials, therefore undermining the drug discovery process in cancer therapies (2).To overcome these issues, several 3D tumor models have been proposed, including tumor spheroids and hydrogel systems, which attempt to recapitulate heterotypic interactions either between tumor and stroma or tumor and extracellular matrix (ECM), respectively (3, 4). These systems have begun to bridge the gap between in vitro and in vivo testing in several aspects, such as cell growth (5), gene expression pattern (6), and chemoresistance (7). However, these models are still unable to recapitulate and adequately examine the effects of other cues present in the tumor microenvironment, such as heterotypic cell−cell...

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Section: Discussionmentioning

confidence: 99%

Flow perfusion effects on three-dimensional culture and drug sensitivity of Ewing sarcoma

Santoro

Lamhamedi-Cherradi

Menegaz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

104

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“…[22][23][24]. However, efficacy of anti-IGF-IR antibodies has been disappointing in clinical trials to date (25)(26)(27)(28)(29)(30).…”

Section: Igf-i Signals By Binding To the Igf-i Receptor (Igf-ir) Or Tmentioning

confidence: 99%

Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin

Friedbichler

Hofmann

Kroez

et al. 2014

Molecular Cancer Therapeutics

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Insulin-like growth factor (IGF) signaling is thought to play a role in the development and progression of multiple cancer types. To date, therapeutic strategies aimed at disrupting IGF signaling have largely focused on antibodies that target the IGF-I receptor (IGF-IR). Here, we describe the pharmacologic profile of BI 836845, a fully human monoclonal antibody that utilizes an alternative approach to IGF signaling inhibition by selectively neutralizing the bioactivity of IGF ligands. Biochemical analyses of BI 836845 demonstrated high affinity to human IGF-I and IGF-II, resulting in effective inhibition of IGF-induced activation of both IGF-IR and IR-A in vitro. Cross-reactivity to rodent IGFs has enabled rigorous assessment of the pharmacologic activity of BI 836845 in preclinical models. Pharmacodynamic studies in rats showed potent reduction of serum IGF bioactivity in the absence of metabolic adverse effects, leading to growth inhibition as evidenced by reduced body weight gain and tail length. Moreover, BI 836845 reduced the proliferation of human cell lines derived from different cancer types and enhanced the antitumor efficacy of rapamycin by blocking a rapamycininduced increase in upstream signaling in vitro as well as in human tumor xenograft models in nude mice. Our data suggest that BI 836845 represents a potentially more effective and tolerable approach to the inhibition of IGF signaling compared with agents that target the IGF-I receptor directly, with potential for rational combinations with other targeted agents in clinical studies. Mol Cancer Ther; 13(2); 399-409. Ó2013 AACR.

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“…сомнения, что маркеры ангиогенеза, продуцируе-мые опухолевым субстратом, могут быть удобной мишенью для таргетной терапии, так же как и слу-жить критериями для прогнозирования течения и исхода заболевания [6,7,17].…”

Section: Discussionunclassified

“…VEGFA189 представлен в сравнительно небольших концентрациях и явля-ется лигандом рецептора VEGFR3, презентирован-ного в основном в лимфатических сосудах [5,6]. VEGFA участвует в регуляции процесса гипоксии и естественным образом связан с фактором, инду-цирующим гипоксию (Hypoxia inducible factor-1, HIF-1) [7]. VEGFC наряду со стимуляцией сосудисто-го эндотелия обеспечивает клеточную миграцию (рецепторами являются VEGFR3, реже VEGFR2), но его ангиогенный потенциал меньше по сравнению с VEGFA [8].…”

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Levels of Angiogenesis Factors Expression in Sarcoma Tissue and Non-Malignant Lesions in Pediatric Patients: Results of a Cross-Sectional Study

Kisialeu¹,

Савицкая²,

Алейникова³

2017

Oncopediatria

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A Phase I Pharmacokinetic and Pharmacodynamic Study of Dalotuzumab (MK-0646), an Anti-Insulin-like Growth Factor-1 Receptor Monoclonal Antibody, in Patients with Advanced Solid Tumors

Cited by 110 publications

References 35 publications

Flow perfusion effects on three-dimensional culture and drug sensitivity of Ewing sarcoma

Flow perfusion effects on three-dimensional culture and drug sensitivity of Ewing sarcoma

Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin

Levels of Angiogenesis Factors Expression in Sarcoma Tissue and Non-Malignant Lesions in Pediatric Patients: Results of a Cross-Sectional Study

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