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21.7.1 Insulin-like growth factor-1 receptors
Insulin-like growth factors (IGFs) are peptides that are part of a complex system often referred to as the IGF “axis.” They have a high sequence homology with insulin and an important role in promotion of cell proliferation and inhibition of apoptosis. The insulin-like growth factor-1 receptor (IGF1R) is a membrane tyrosine kinase receptor with 70% homology to the insulin receptor. When it is activated by its ligands IGF1, IGF2, or by insulin, it transmits a signal to two adaptor proteins: the insulin receptor substrate-1 (IRS1) and the Src homologous and collagen (Shc) [52]. Both adaptor proteins lack intrinsic enzymatic activity, but they possess various domains that allow them to recruit different signaling molecules. Shc is recruited by activated cell surface receptors (like IGF1R) or by integrins, then being phosphorylated by receptor tyrosine kinases (e.g., EGFR) or cytosolic tyrosine kinases. Phosphorylated Shc can then interact with Grb2, leading to the activation of different pathways such as MAPK, PI3K/Akt and Ras homolog family member A (RhoA) that depend on the activation of Ras (Fig. 21.18).
Figure 21.18. Activation of Ras by IGFR via Shc recruitment (IGF1R—insulin-like growth factor-1 receptor; Shc—Src homologous and collagen; GAB1—GRB2-associated-binding protein 1; Grb—growth factor receptor-bound protein 2; SoS—Son of Sevenless; Ras—rat sarcoma protein; GDP—guanosine diphosphate).
IGF1R is particularly important in the establishment and maintenance of the transformed phenotype, in mediating proliferation, and in the survival of tumor cells with anchorage-independent growth. IGF1R also exerts antiapoptotic activity and has a substantial influence on the control of the cell and body size, enabling transformed cells to form macroscopic tumors and to survive the process of detachment required for metastasis [53].
Various strategies, such as anti-IGF-1R antibodies, IGF-1 mimetic peptides, antisense oligonucleotides, and IGF-1R-specific peptide aptamers, as well as the induction of targeted degradation of IGF-1R and expression of dominant-negative IGF-1R mutants, have been explored to inhibit IGF-1R signaling. Targeting the intracellular kinase domain of IGF-1R with small molecules (most commonly ATP antagonists) has gained considerable attention, but because of the high sequence homology of the kinase domains of the IGF-1R and insulin receptor (IR) this strategy may be associated with metabolic adverse effects.
Since 2000, several agents targeting IGF1-IGF1R signaling have shown antitumor activity in preclinical studies which led to the evaluation of different drug candidates in clinical trials [54]. Although antibody-based anti-IGF1 signaling therapeutic development was at the forefront, many efforts were directed to design and develop small-molecule IGF1R kinase inhibitors [55]. Since these compounds cannot be considered peptidomimetics, they are outside the scope of this chapter.
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URL: https://www.sciencedirect.com/science/article/pii/B9780128201411000108
2.2 Insulin-like growth factor receptor-1
Insulin-like growth factor receptor-1 (IGFR-1) is a transmembrane protein that holds a significant role in promoting oncogenic transformation, growth and survival of cancer cells [17]. IGFR-1 activation triggers a cascade of reactions involving two main signal transduction pathways [18]: one activates Ras–Raf–MAPK network and the other involves PI3K; therein showing distinct similarities to the family of ERBB receptor protein family (Fig. 1). Deregulation of IGF signaling has been described in several tumor types, including lung cancer. Furthermore, elevated IGF-1 levels have been associated with increased risk of lung cancer, while increased quantity of IGF-Binding Protein 3 has been correlated with reduced risk [17]. Expression of IGFR-1 has been detected in squamous cell lung carcinomas, although no survival difference has been observed between IGFR-1 positive and negative surgically resected NSCLC patients [19]. Monoclonal antibodies and TKIs against IGFR-1 have been developed and currently being tested in the clinical setting [20].
Fig. 1. Major molecular networks participating in respiratory epithelium carcinogenesis and potential ways of targeting.
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URL: https://www.sciencedirect.com/science/article/pii/S0304383510001515
Abstract
The insulin-like growth factor-1 receptor (IGF-1R) is a central component of lung cancer signal transduction pathways. A phase III study failed for carboplatin, paclitaxel, with or without figitumumab in first-line treating metastatic non-small cell lung cancer (NSCLC). There is an urgent need for a better understanding of signaling in IGF system. Insulin-like growth factor-binding proteins (IGFBPs) function as modulators for IGF signaling through sequestration of IGFs in serum and the extracellular fluid. IGFBPs can also act as transporters or modulators for IGF action and insulin action. IGFBPs have attracted increased attention for their lung cancer-related role in recent years. Recent studies have demonstrated the critical role of IGFBPs in risk assessment, early detection, prognosis evaluation, and drug resistance appraisal for lung cancer. These observations suggest a potential new approach to understand the pathogenesis of lung cancer, have important clinical implications, while additional investigations are necessary.
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URL: https://www.sciencedirect.com/science/article/pii/S000989811730027X
Insulin-like growth factor 1 receptor inhibitors
Insulin-like growth factor 1 (IGF-1) is central to the pathophysiology of multiple myeloma. A small-molecule IGF-1R tyrosine kinase inhibitor, NVP-ADW742 (Novartis Pharma AG, Switzerland), has shown significant cytotoxicity in vitro and in vivo in MM.98 Targeting the IGF-1 receptor using picropodophyllin in the mouse 5T2 MM model also showed strong anti-tumor activity and a significant OS advantage for treated mice.99 The multiple roles of this signaling pathway were also reflected in significant inhibition of tumor-associated angiogenesis and osteolysis.
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URL: https://www.sciencedirect.com/science/article/pii/S1521692607000746
3.2.3 Anti-insulin-like growth factor 1 (IGF-1) therapy
Insulin-like growth factor-1 receptor (IGF-1R, located in 15q26.3) is a cell surface receptor with tyrosine kinase activity that activates the PI3K/Akt/mTOR and RAS/RAF/MAPK signaling pathways by binding IGF-1 or IGF-2 ligand [30]. The protein or mRNA expression of IGF-1R, but not IGF-1R gene copy number, was reported to be higher in lung SQCC than in other histologic subtypes [31]. In a phase II study with NSCLC, CP-751871 (figitumumab) with paclitaxel and carboplatin showed a response rate of 78% in patients with advanced SQCC [32]. However, two subsequent phase III studies of figitumumab with paclitaxel/carboplatin or erlotinib were discontinued due to non-significant survival benefit and increased toxicity [33,34]. A phase II study is ongoing to compare anti-tumor activity of AXL1717, a small-molecule IGF-1R inhibitor, with docetaxel as a second-line treatment of advanced lung SQCC (NCT01561456).
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URL: https://www.sciencedirect.com/science/article/pii/S0169500213000743
The insulin-like growth factor receptor (IGF-1R) belongs to a family of transmembrane protein tyrosine kinases, which include the highly homologous insulin receptor and the insulin receptor related receptors [1,2]. The functional IGF-1R contains two α and two β subunits which are joined by disulfide bridges to form a heterotetrameric receptor complex. The α chains are exclusively extracellular and bind the ligands IGF-1, IGF-2 or insulin; the β chains comprise a short extracellular segment, a transmembrane region, an intracellular tyrosine kinase domain and a COOH-terminal region [3]. Ligand binding leads to a conformational change of the receptor that triggers autophosphorylation of three tyrosine residues in the activation loop within the kinase domain [4] resulting in an increase in catalytic activity. Tyrosine residues within the juxtamembrane region and COOH-terminal serine residues become phosphorylated, and as a consequence induce recruitment of downstream signaling components including insulin receptor substrates (IRS)-1 and -2, Shc, and Grb10 [5]. This in turn leads to activation of distinct signaling pathways, including the phosphatidylinositol 3-kinase (PI 3K)-Akt pathway and the Ras/Raf/mitogen-activated protein (MAP) kinase pathway [6].
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URL: https://www.sciencedirect.com/science/article/pii/S1096637404000280
Insulin/Insulin-Like Growth Factor Receptors
The insulin and insulin-like growth factors receptors play key roles in embryonic growth and development, signaling through membrane receptors with intrinsic tyrosine kinase activity. In XY compound KO mice deficient in the insulin receptor, insulin-like growth factor 1 receptor, and a related receptor, Insulin-related receptor (Irr), testes development was impaired and ovaries developed despite expression of Sry (115). Although the underlying mechanism is not known, this finding suggests that action of these growth factors via their cognate membrane receptors is essential for proliferation of the Sertoli cell precursors, and hence for testes development.
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URL: https://www.sciencedirect.com/science/article/pii/B9780125154000500130
Insulin-like growth factor
The insulin-like growth factor system consists of three ligands, two receptors, and six insulin-like growth factor binding proteins (IGFBPs). Insulin-like growth factor 1 (IGF-I) and insulin-like growth factor 1 receptor (IGF-I-R) are the components of the system with the greatest relevance to brain tumor formation. The IGF-I pathway is active during fetal brain development and relatively quiescent in normal mature neural tissue, but emerges again to drive growth of malignant brain tumors (Trojan 2007). The role of IGFBPs in glioma formation is less clear; they bind with IGF-I and increase its half-life, while also competing with IGF-I-R for IGF-I binding. Elevated plasma levels of IGFBPs have been demonstrated in patients with several types of solid tumors, and elevated plasma IGFBP-2 has been shown to correlate with increased tumor recurrence and decreased disease-free survival in patients with glioblastoma multiforme (Lin et al 2009). As with previously discussed growth factor systems, both the PI3K-Akt-mTOR and RAS-RAF-MEK-MAPK pathways are involved in IGF-I-R pathway signal transduction (Trojan 2007).
No selective inhibitors of the IGF pathway have yet been evaluated in clinical trials for treatment of central nervous system tumors. SCH 717454, a fully human antibody directed against the IGF-1-R is currently being examined in phase II studies for the treatment of colorectal cancer and osteosarcoma or Ewing's sarcoma. Multiple IGF-I-R tyrosine kinase inhibitor small molecules are in development. Agents such as BMS-754807 and OSI-906 are being evaluated in phase I trials of non-CNS malignancies, and still more options are in pre-clinical testing.
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URL: https://www.sciencedirect.com/science/article/pii/B9780443069673000065
The insulin-like growth factor 1 receptor (IGF-1R) is an important signaling molecule in cancer cells and plays an essential role in the establishment and maintenance of the transformed phenotype. Inhibition of IGF-1R signaling thus appears to be a promising strategy to interfere with the growth and survival of cancer cells. Different classes of molecules, e.g., antisense RNA, monoclonal antibodies and dominant negative IGF-1R gene variants, have been employed towards this aim. These agents have been able to reverse the transformed phenotype in several rodent and human cancer cell lines. The application of peptide aptamers specifically binding to the IGF-1R represents a novel approach to target IGF-1R signaling. The integration of peptide aptamers into targeted protein degradation vehicles and their transduction into cells allows the temporary elimination of the receptor protein. This review summarizes recently published data about inhibition of IGF-1R signaling and provides a perspective on upcoming possibilities.
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URL: https://www.sciencedirect.com/science/article/pii/S1096637404000280
Insulin-like growth factor 1 (IGF-1) is an old friend of the heart. Despite the well-known protective effects of IGF-1 on cardiac function and the antiapoptotic effects of this peptide, novel evidence opens new questions to this longstanding relationship.
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How do the multiple signaling pathways triggered by IGF-1 receptor (IGF-1R) interact with each other? What lies further than extracellular signal-regulated kinase (ERK)/Akt/Ca2+ activation toward heart function? Do these signaling pathways regulate cardiac fibroblast or endothelial cell function? •
Which are the specific downstream signaling pathways of the different pools of IGF-1R and their role in regulating cardiomyocyte survival, hypertrophy, metabolism, proliferation? What drives IGF-1R to such specific subcellular compartments? •
What is the relevance of the hybrid IGF-1R/insulin receptors on cardiovascular disease? •
Does a crosstalk exist between insulin receptor and IGF-1R in the heart under physiological and pathological conditions? Is one pathway more beneficial than the other? •
Will stem cell therapy of cardiac progenitors be able to provide concrete treatment opportunities? Is IGF-1 a key regulator of this outcome?
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URL: https://www.sciencedirect.com/science/article/pii/S1043276013002075