Cancer research (Chicago, Ill.), 2011-02, Vol.71 (3), p.1029-1040
2011
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Details
- Autor(en) / Beteiligte
- Titel
- Dual IGF-I/II-Neutralizing Antibody MEDI-573 Potently Inhibits IGF Signaling and Tumor Growth
- Ist Teil von
- Cancer research (Chicago, Ill.), 2011-02, Vol.71 (3), p.1029-1040
- Ort / Verlag
- Philadelphia, PA: American Association for Cancer Research
- Erscheinungsjahr
- 2011
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Insulin-like growth factors (IGF), IGF-I and IGF-II, are small polypeptides involved in regulating cell proliferation, survival, differentiation, and transformation. IGF activities are mediated through binding and activation of IGF-1R or insulin receptor isoform A (IR-A). The role of the IGF-1R pathway in promoting tumor growth and survival is well documented. Overexpression of IGF-II and IR-A is reported in multiple types of cancer and is proposed as a potential mechanism for cancer cells to develop resistance to IGF-1R-targeting therapy. MEDI-573 is a fully human antibody that neutralizes both IGF-I and IGF-II and inhibits IGF signaling through both the IGF-1R and IR-A pathways. Here, we show that MEDI-573 blocks the binding of IGF-I and IGF-II to IGF-1R or IR-A, leading to the inhibition of IGF-induced signaling pathways and cell proliferation. MEDI-573 significantly inhibited the in vivo growth of IGF-I- or IGF-II-driven tumors. Pharmacodynamic analysis demonstrated inhibition of IGF-1R phosphorylation in tumors in mice dosed with MEDI-573, indicating that the antitumor activity is mediated via inhibition of IGF-1R signaling pathways. Finally, MEDI-573 significantly decreased (18)F-fluorodeoxyglucose ((18)F-FDG) uptake in IGF-driven tumor models, highlighting the potential utility of (18)F-FDG-PET as a noninvasive pharmacodynamic readout for evaluating the use of MEDI-573 in the clinic. Taken together, these results demonstrate that the inhibition of IGF-I and IGF-II ligands by MEDI-573 results in potent antitumor activity and offers an effective approach to selectively target both the IGF-1R and IR-A signaling pathways.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0008-5472eISSN: 1538-7445DOI: 10.1158/0008-5472.can-10-2274Titel-ID: cdi_proquest_miscellaneous_849010966
- Format
- –
- Schlagworte
- Animals, Antibodies, Monoclonal - immunology, Antibodies, Monoclonal - pharmacology, Antibodies, Neutralizing - immunology, Antibodies, Neutralizing - pharmacology, Antineoplastic agents, Biological and medical sciences, Cell Line, Female, Fluorodeoxyglucose F18, Humans, Insulin-Like Growth Factor I - antagonists & inhibitors, Insulin-Like Growth Factor I - immunology, Insulin-Like Growth Factor I - metabolism, Insulin-Like Growth Factor II - antagonists & inhibitors, Insulin-Like Growth Factor II - immunology, Insulin-Like Growth Factor II - metabolism, Medical sciences, Mice, Mice, Knockout, Neoplasms, Experimental - diagnostic imaging, Neoplasms, Experimental - drug therapy, Neoplasms, Experimental - immunology, Neoplasms, Experimental - metabolism, Pharmacology. Drug treatments, Phosphorylation - drug effects, Positron-Emission Tomography, Protein Isoforms, Radiopharmaceuticals, Receptor, IGF Type 1 - antagonists & inhibitors, Receptor, IGF Type 1 - metabolism, Receptor, Insulin - antagonists & inhibitors, Receptor, Insulin - metabolism, Signal Transduction - drug effects, Tumors, Xenograft Model Antitumor Assays