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Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future Combination Studies

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Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future Combination Studies Targ Oncol (2017) 12:571–597 DOI 10.1007/s11523-017-0514-5 REVIEW ARTICLE Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future Combination Studies Aaron Simpson1 & Wilfride Petnga1 & Valentine M. Macaulay 1 & Ulrike Weyer-Czernilofsky2 & Thomas Bogenrieder2,3 Published online: 16 August 2017 # The Author(s) 2017. This article is an open access publication Abstract Despite a strong preclinical rationale for targeting preclude their use at clinically effective doses. Conversely, the insulin-like growth factor (IGF) axis in cancer, clinical IGF-1/IGF-2 ligand-neutralizing mAbs inhibit proliferative/ studies of IGF-1 receptor (IGF-1R)-targeted monotherapies anti-apoptotic signaling via IGF-1R and INSR-A, without have been largely disappointing, and any potential success compromising the metabolic function of INSR-B. Therefore, has been limited by the lack of validated predictive bio- combination regimens that include these agents may be more markers for patient enrichment. A large body of preclinical efficacious and tolerable versus IGF-1R-targeted combinations. evidence suggests that the key role of the IGF axis in cancer Herein, we review the preclinical and clinical experience with is in driving treatment resistance, via general proliferative/ IGF-targeted therapies to-date, and discuss the rationale for survival mechanisms, interactions with other mitogenic sig- future combination approaches as a means to overcome treat- naling networks, and class-specific mechanisms such as DNA ment resistance. damage repair. Consequently, combining IGF-targeted agents with standard cytotoxic agents, other targeted agents, endo- Key Points crine therapies, or immunotherapies represents an attractive therapeutic approach. Anti-IGF-1R monoclonal antibodies Therapeutic targeting of insulin-like growth factor (IGF) (mAbs) do not inhibit IGF ligand 2 (IGF-2) activation of the signaling has been investigated in many types of human insulin receptor isoform-A (INSR-A), which may limit their cancer. anti-proliferative activity. In addition, due to their lack of spec- ificity, IGF-1R tyrosine kinase inhibitors are associated with Interactions between the IGF axis and other signaling hyperglycemia as a result of interference with signaling networks can result in resistance to therapies that target through the classical metabolic INSR-B isoform; this may individual signaling pathways. IGF-targeted combination therapy represents a promising Aaron Simpson and Wilfride Petnga are joint first authors approach to anti-cancer therapy, as supported by a large Enhanced content body of preclinical evidence. To view enhanced content for this article go to http://www.medengine. com/Redeem/5D48F06008D136AC. * Thomas Bogenrieder [email protected] 1 The IGF Axis and Its Role in Tumor Biology 1 Department of Oncology, University of Oxford, Oxford, UK 2 Boehringer Ingelheim RCV, Dr. Boehringer Gasse 5-11, 1.1 IGF: Dramatis Moleculae 1121 Vienna, Austria 3 Department of Urology, University Hospital Grosshadern, Insulin-like growth factor (IGF) signaling plays an important Ludwig-Maximilians-University, Marchioninistrasse 15, role in regulating growth and development in normal human 81377 Munich, Germany tissues by promoting cellular proliferation and differentiation 572 Targ Oncol (2017) 12:571–597 and preventing apoptosis [1, 2]. The IGF axis comprises insu- The IGF system also encompasses various IGF-binding lin and two related ligands, IGF ligands 1 and 2 (IGF-1 and proteins (IGFBPs), IGFBP-specific proteases, and IGFBP- IGF-2) that regulate cellular processes by interacting with spe- related peptides, which bind to and modify the activity of cific cell-surface receptors (Fig. 1)[1, 5]. The IGF-1 receptor IGF ligands (Fig. 1)[1, 5]. Aside from their endocrine role (IGF-1R) is a heterotetrameric receptor with two extracellular, in IGF transport, IGFBPs have many additional, IGF- ligand-binding domains (alpha subunits) and two transmem- independent biological functions that modulate cellular brane beta subunits that contain the kinase domain; the alpha growth and survival [8]. For example, in breast cancer, and beta domains are linked by disulfide bonds [6]. Along IGFBP3 has been shown to interact with the epidermal growth with the insulin receptor (INSR), IGF-1R is a member of the factor receptor (EGFR) and can influence the response to receptor tyrosine kinase (RTK) class 2 family of receptors DNA damage [9]. A comprehensive assessment of IGFBP (insulin receptor family) [1, 3]. IGF-1R binds the IGF ligands biology is beyond the scope of this review. However, for more with varying affinities depending on the cell type and exper- details, please refer to a 2014 review paper by Baxter [8]. imental conditions, both IGFs binding with higher affinity than insulin. IGF-2 also binds to INSR-A, a fetal isoform that 1.2 The IGF Axis in Cancer is overexpressed in some tumors, and to IGF-2 receptor (IGF- 2R), a structurally unrelated receptor that lacks tyrosine kinase Increased expression of IGF-1R and/or circulating levels of activity and serves as a scavenger for circulating IGF-2 [7]. IGF ligands has been observed in various cancers, including In addition to INSR-A, which binds insulin and IGF-2 with Ewing sarcoma, breast cancer, prostate cancer, pancreatic can- equal affinity and transmits proliferative/survival signals, cer, melanoma, and many other tumor types; this overexpres- INSR exists in the classical metabolic isoform, INSR-B, sion is associated with faster disease progression and a poor which binds insulin [1] and regulates glucose uptake [5, 7]. prognosis in some tumors [10–12]. Moreover, the presence of Among these components, the IGF axis includes hybrid re- a functional IGF-1R has been shown to be essential for ma- ceptors composed of IGF-1R and INSR isoforms; these IGF- lignant transformation [13]. IGF-1R overexpression can result 1R/INSR heterodimers contain predominantly INSR-A in ma- from the loss of tumor suppressors, including p53, breast can- lignant cells, and bind IGF-1, IGF-2, and insulin [7]. cer gene-1 (BRCA1), von Hippel-Lindau protein and Wilms’s Insulin IGF-1 IGFBPs IGF-2 Free IGF IGFBP ligands fragments IGFBP protease INSR-A/ IGF-1R/ IGF-1R/ INSR-B INSR-B INSR-A INSR-B INSR-A IGF-1R IGF-2R Extracellular matrix Cytoplasm Mainly glucose homeostasis Proliferation/growth/survival/metastasis Fig. 1 Components of the insulin/IGF axis. The IGF axis consists of cross-bind to each other’s receptor, albeit with much weaker affinity than ligands (insulin, IGF-1, and IGF-2), receptors (INSR, IGF-1R, IGF-2R, that for the preferred ligand. Activation of the INSR-B isoform regulates and IGF-1R/INSR hybrid receptors), IGFBPs 1 to 7, and IGFBP glucose metabolism, while activation of IGF-1R, INSR-A, and IGF-1R/ proteases. The IGF ligands bind their receptors and binding proteins INSR hybrid receptors promotes cellular growth, proliferation, survival, with high affinity. IGFBPs bind tightly to IGF ligands, influencing and metastasis. IGF-2R is an unrelated monomeric receptor that acts as a binding to their receptors; IGFBP proteases cleave the IGFBPs into scavenger for circulating IGF-2 [1, 3, 4]. IGF-1/−2 insulin-like growth fragments with lower affinity for the IGF ligands, thereby increasing factor ligand 1/2, IGFBP IGF binding protein, IGF-1R/IGF-2R type 1/ free IGF-1 and IGF-2 bioavailability. IGF-1/IGF-2 and insulin can type 2 IGF receptor, INSR insulin receptor Targ Oncol (2017) 12:571–597 573 tumor suppressor WT1 [14–16]. However, IGF signaling in IGF-1R depletion or inhibition has been shown to attenuate tumor cells is driven by the presence of the ligands rather than repair of radiation-induced double strand breaks (DSBs) in pros- receptor aberrations [14], and there is evidence that a low tate cancer cell lines [31, 33]. circulating IGF-1 concentration can protect against tumori- On activation of IGF-1R or IGF-1R/INSR hybrid recep- genesis [17, 18]. IGF ligands can be delivered to the IGF-1R tors, downstream signal transduction occurs via two major from distant (endocrine) or nearby (paracrine) sources, with pathways (Fig. 2)[5, 34]. Activation of the RAS/mitogen- circulating free-ligand levels regulated by the different activated protein kinase (MAPK) cascade results in the tran- IGFBPs [2]. In addition, autocrine production of IGF ligands scription of genes that drive cellular proliferation, such as the in some tumor cells which themselves express IGF-1R can D-type cyclins. Activation of cyclin D/cyclin-dependent ki- also contribute to tumor proliferation [19, 20]. nase 4 (CDK4) complexes leads to increased E2F-dependent In addition to IGF-1 and IGF-1R, overexpression of IGF-2 transcription, via liberation of the E2F transcription factor and INSR-A is reported in a wide range of human cancers, from sequestration by the retinoblastoma protein, so driving including breast, colorectal, prostate, and lung cancers, and is passage through the G1/S-phase transition during cell-cycle also associated with a poor prognosis [21–23]. In preclinical progression [35–37]. In parallel, signaling via the phos- studies, direct upregulation of IGF-2 in response to chemo- phatidylinositol 3-kinase/protein kinase-B (PI3K/Akt) path- therapy was shown to enhance the aggressive properties of way confers protection from apoptosis [5]. In addition, Akt castration-resistant prostate cancer (CRPC) models by activat- acts on cell-cycle regulatory proteins, inducing inhibitory ing INSR-A and/or IGF-1R/INSR-A hybrid receptors; thus, phosphorylation of glycogen synthase kinase-3 beta, p21, both IGF ligands can function as part of an adaptive mecha- and p27, to stabilize type-D cyclins and promote cell-cycle nism that promotes resistance and tumorigenicity in certain progression [38–40]. Akt also promotes cyclin D function via cancers, during or after treatment [23, 24]. Furthermore, in induction of the mammalian target of rapamycin complex 1 tumor cells where IGF-1R and INSR are co-expressed, upreg- (mTORC1), by preventing its inhibition by tuberous sclerosis ulated INSR can compensate for IGF-1R inhibition, thereby complex (TSC) proteins.
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