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      IGF-IR Targeted Therapy: Past, Present and Future

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          Abstract

          The IGF-I receptor (IGF-IR) has been studied as an anti-cancer target. However, monotherapy trials with IGF-IR targeted antibodies or with IGF-IR specific tyrosine kinase inhibitors have, overall, been very disappointing in the clinical setting. This review discusses potential reasons why IGF-I R targeted therapy fails to inhibit growth of human cancers. It has become clear that intracellular signaling pathways are highly interconnected and complex instead of being linear and simple. One of the most potent candidates for failure of IGF-IR targeted therapy is the insulin receptor isoform A (IR-A). Activation of the IR-A by insulin-like growth factor-II (IGF-II) bypasses the IGF-IR and its inhibition. Another factor may be that anti-cancer treatment may reduce IGF-IR expression. IGF-IR blocking drugs may also induce hyperglycemia and hyperinsulinemia, which may further stimulate cell growth. In addition, circulating IGF-IRs may reduce therapeutic effects of IGF-IR targeted therapy. Nevertheless, it is still possible that the IGF-IR may be a useful adjuvant or secondary target for the treatment of human cancers. Development of functional inhibitors that affect the IGF-IR and IR-A may be necessary to overcome resistance and to make IGF-IR targeted therapy successful. Drugs that modify alternative downstream effects of the IGF-IR, so called “biasing agonists,” should also be considered.

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          Most cited references 58

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          Insulin-like growth factors and their binding proteins: biological actions.

           D Clemmons,  J Jones (1995)
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            The insulin and insulin-like growth factor receptor family in neoplasia: an update.

            Although several early phase clinical trials raised enthusiasm for the use of insulin-like growth factor I receptor (IGF1R)-specific antibodies for cancer treatment, initial Phase III results in unselected patients have been disappointing. Further clinical studies may benefit from the use of predictive biomarkers to identify probable responders, the use of rational combination therapies and the consideration of alternative targeting strategies, such as ligand-specific antibodies and receptor-specific tyrosine kinase inhibitors. Targeting insulin and IGF signalling also needs to be considered in the broader context of the pathophysiology that relates obesity and diabetes to neoplasia, and the effects of anti-diabetic drugs, including metformin, on cancer risk and prognosis. The insulin and IGFI receptor family is also relevant to the development of PI3K-AKT pathway inhibitors.
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              Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease.

              In mammals, the insulin receptor (IR) gene has acquired an additional exon, exon 11. This exon may be skipped in a developmental and tissue-specific manner. The IR, therefore, occurs in two isoforms (exon 11 minus IR-A and exon 11 plus IR-B). The most relevant functional difference between these two isoforms is the high affinity of IR-A for IGF-II. IR-A is predominantly expressed during prenatal life. It enhances the effects of IGF-II during embryogenesis and fetal development. It is also significantly expressed in adult tissues, especially in the brain. Conversely, IR-B is predominantly expressed in adult, well-differentiated tissues, including the liver, where it enhances the metabolic effects of insulin. Dysregulation of IR splicing in insulin target tissues may occur in patients with insulin resistance; however, its role in type 2 diabetes is unclear. IR-A is often aberrantly expressed in cancer cells, thus increasing their responsiveness to IGF-II and to insulin and explaining the cancer-promoting effect of hyperinsulinemia observed in obese and type 2 diabetic patients. Aberrant IR-A expression may favor cancer resistance to both conventional and targeted therapies by a variety of mechanisms. Finally, IR isoforms form heterodimers, IR-A/IR-B, and hybrid IR/IGF-IR receptors (HR-A and HR-B). The functional characteristics of such hybrid receptors and their role in physiology, in diabetes, and in malignant cells are not yet fully understood. These receptors seem to enhance cell responsiveness to IGFs.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/112830
                URI : http://frontiersin.org/people/u/160115
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                23 December 2014
                2014
                : 5
                Affiliations
                1Department of Internal Medicine, Division of Endocrinology, Erasmus MC , Rotterdam, Netherlands
                Author notes

                Edited by: Antonino Belfiore, University “Magna Graecia” of Catanzaro, Italy

                Reviewed by: Roberta Malaguarnera, University “Magna Graecia” of Catanzaro, Italy; Giovanni Vitale, Universita ′ degli Studi di Milano, Italy; Francesca Peruzzi, Louisiana State University Health Sciences Center, USA

                *Correspondence: Joseph A. M. J. L. Janssen, Department of Internal Medicine, Erasmus MC, Room D-443, ‘s-Gravendijkwal 230, Rotterdam 3015 CE, Netherlands e-mail: j.a.m.j.l.janssen@ 123456erasmusmc.nl

                This article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology.

                Article
                10.3389/fendo.2014.00224
                4275034
                Copyright © 2014 Janssen and Varewijck.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 64, Pages: 7, Words: 5362
                Categories
                Endocrinology
                Mini Review

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