乳腺癌治疗中胰岛素样生长因子的靶向治疗的应用

Targeting insulin-like growth factor in breast cancer therapeutics.

2013-01-04 10:53点击：328次发表评论

作者：Karamouzis MV, Papavassiliou AG.

期刊： 《EUR J CANCER》2013年1月期卷

Targeting insulin-like growth factor in breast cancer therapeutics

Michalis V. Karamouzis^,,
Athanasios G. Papavassiliou

Molecular Oncology Unit, Department of Biological Chemistry, University of Athens Medical School, 11527 Athens, Greece

http://dx.doi.org/10.1016/j.critrevonc.2012.02.010, How to Cite or Link Using DOI

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Abstract

The insulin-like growth factor (IGF) pathway holds crucial role in cell growth, differentiation and proliferation. Aberrant regulation of the IGF system has been attributed to the pathogenesis of breast cancer and has been shown to contribute to various stages of breast carcinogenesis. Therefore, targeting the IGF-related axis represents a promising strategy, mainly aiming to bypass the resistance of currently employed treatment options in breast cancer patients. Nevertheless, major limitations have aroused despite the early stage of clinical development of various IGF-system modulators. The present review highlights the current status and considers the future perspectives of IGF-system targeting in breast cancer therapeutics.

Keywords

Breast cancer;
Insulin-like growth factor (IGF);
IGF receptor;
Monoclonal antibody;
Signal transduction;
Tyrosine kinase

1. Introduction

Breast cancer is the second most common non-skin cancer with approximately 430,000 cases occurring each year in Europe [1]. It is the second leading cause of cancer-related death in women in the Western world, after lung cancer [2], with about 132,000 deaths each year and a 5-year overall survival of approximately 79% [3]. Although the majority of patients are diagnosed in earlier and potential curable stages, metastatic breast cancer (MBC) remains an unsolved clinical entity. Systemic chemotherapy and/or hormone therapy represent the treatment cornerstone of MBC patients. Efficacious chemotherapeutic combinations with the addition of novel molecularly-targeting agents (e.g. trastuzumab, lapatinib, bevacizumab) have resulted in further survival prolongation [4], [5], [6], [7], [8] and [9]. However, new therapeutic strategies are needed in order to improve clinical results. The identification and further modulation of molecular targets with central role in breast carcinogenesis represent a rational approach for prevention and treatment [10], [11], [12] and [13]. Data published during the last decade has implicated insulin-like growth factor (IGF) and its signaling cascade in the development and progression of breast cancer [14].

Herein, we will discuss the role of IGF pathway in breast tumorigenesis and the perspectives of the targeting strategies that are being developed and tested so far in breast cancer therapeutics.

2. The IGF pathway

2.1. Ligands and associated proteins

The IGF family includes the peptides IGF-1, IGF-2 and insulin [15]. IGF-1 and IGF-2 are peptide growth factors that play an important role in the growth and development of several tissues. IGF-1 is primarily produced by the liver under the regulation of growth hormone (GH) [15]. The bioavailability of IGFs is regulated by a family of high-affinity binding proteins, the IGF-binding proteins (IGFBPs), which serve to protect them from degradation by proteases [16]. Additionally, IGFBPs regulate availability of IGF at the cellular microenvironment by competing with the receptor for ligand binding. There are six members in the IGFBP family and they form complexes with IGF-1 and IGF-2 with the same affinity as the IGF receptor [16]. Furthermore, there is an increasing volume of data supporting that IGFBPs have growth regulatory actions that are independent of their capacity to bind IGFs (Fig. 1) [15].

Fig. 1. The IGF-system components and downstream effector molecules. BAD, Bcl-associated dimer; FKHR, forkhead transcription factor; Grb2, growth factor receptor-binding protein 2; GSK-3, glycogen synthase kinase-3; IGF, insulin-like growth factor; IGF-1R, IGF-1 receptor; IGFBPs, IGF-binding proteins; IR, insulin receptor; IRS-1, insulin receptor substrate-1; MAPK, mitogen-activated protein kinase; MEK, MAPK/extracellular signal-regulated kinase (ERK) kinase; mTOR, mammalian target of rapamycin; P, phosphate groups; PI-3K, phosphatidylinositol-3 kinase; PTEN, phosphatase and tensin homologue deleted on chromosome 10; Sos, son of sevenless.

Figure options

2.2. Receptors

Two receptors are included in the IGF pathway; the IGF receptor type 1 (IGF-1R) and the IGF receptor type 2 (IGF-2R). Both IGF-1 and IGF-2 exert their biological activity through signaling via the IGF-1R, whilst IGF-2 can also bind and activate the insulin receptor (IR) (Fig. 1 and Table 1).

Table 1. IGF/IGFR pathway components in breast carcinomas.

Receptor	Expression in breast cancer cells	Relative binding affinity
IGF-1R	↑	IGF-1 ≥ IGF-2
IR-A	↑	INS > IGF-2 ≫ IGF-1
HR-A	↑	IGF-1 ≥ IGF-2 ≫ INS
IR-A/IR-B	↑	INS > IGF-2 ≫ IGF-1
Atypical IGF-1R	↑	IGF-1 ∼ INS
IR-B	↔ ↑	INS
HR-B	↔ ↑	IGF-1 ≥ IGF-2

IR, insulin receptor; HR, hybrid receptor; INS, insulin; ↔, no difference.

Table options

IGF-1R is a transmembrane heterotetrameric protein consisting of two polypeptide chains; each chain has an extracellular, ligand-binding α-subunit and an intracellular β-subunit which bears tyrosine kinase (TK) activity. IGF-2R lacks TK activity and is thus considered incapable of activating intracellular signaling pathways [17]. Furthermore, the cells express a hybrid IGF-1R–IR receptor comprising one αβ chain of IGF-1R and one of IR which has high affinity for IGF-1 and IGF-2, similar to that of IGF-1R [18] and [19]. Upon binding of ligands to the extracellular part of the receptor, the receptor is potentiated and the intracellular TK domain is phosphorylated. Activation of the TK domain leads to phosphorylation of several substrates such as insulin receptor substrate proteins (IRS1-4), a signal regulatory protein family; activation triggers a cascade of reactions involving two main signal transduction pathways: the Ras–Raf–mitogen-activated protein kinase (MAPK) network and the phosphatidylinositol-3 kinase (PI-3K)/Akt pathway (Fig. 1). Certain transcription factors have been identified to be impaired by this IGF-mediated signaling process and involved in breast carcinogenesis [20] and [21]. IR has two different isoforms generated by alternative splicing of exon 11; the B-isoform (IR-B) that bears 11 extra amino-acids encoded by exon 11 and the A-isoform (IR-A) that lacks these amino acids and is more highly expressed in fetal tissue [22]. It has been also described that IGF-1R and IRs can translocate to the nucleus and auto-regulate the activity of IGF/IGF-1R pathway in breast cancer cells depending on the estrogen receptor status [23].

3. The IGF pathway and breast cancer

The IGF pathway has been found to be implicated in breast carcinogenesis [24]. IGF-1R is over-expressed in about 90% of breast cancer cases and IGF-1R levels are higher in cancer cells than in normal breast tissue or in benign mammary tumors [25]. Furthermore, breast cancer cells over-express both IGF-1R and IR-A and that leads potentially to formation of hybrid IGF-1R–IR-A receptors (HRs) as well [26] and [27].

Sell et al. demonstrated that IGF-1R plays a major role in the transformation of fibroblasts via the simian virus 40 large T-antigen transformation pathway and that fibroblasts lacking IGF-1R cannot be transformed[28]. Preclinical data in tumor xenografts revealed that IGF-1 plays an important role in stimulation of tumor growth in an autocrine or paracrine manner [15].

Additionally, IGF-1R has been associated with the cell's metastasizing potential. Dunn et al. have shown that inhibition of IGF-1R resulted in suppression of adhesion, invasion and metastasis of breast cancer cells, while that inhibition did not significantly suppress the growth of the primary tumor [29]. Similarly, Sachdev et al. demonstrated that xenografts that expressed a truncated IGF-1R exhibited no metastatic potential albeit proliferation was not influenced [30]. The IGF/IGF-1R downstream signaling pathways have been recently shown also to be involved in the metastatic cascade in breast cancer cells [31].

Over-expression of IGF-1R has been associated with poor prognosis in patients with early breast cancer [32]. Moreover, epidemiological data from the large Nurses’ Health Study yielded that higher levels of circulating IGF-1 were associated with higher risk of breast cancer development [33]. Similarly, a recently published pooled analysis of 17 trials by the Endogenous Hormones and Breast Cancer Collaborative Group demonstrated that circulating IGF-1 was positively associated with breast cancer risk and that association was not substantially modified by IGFBP-3, primarily in women with estrogen-receptor (ER) positive tumors[34].

Data from human breast tumors has demonstrated that IGF-1R is over-expressed and hyper-phosphorylated. However, the prognostic utility of IGF-1R expression in breast carcinomas are up to now conflicting, mainly due to technical issues (e.g. optimal cut-off point value defining receptor over-expression) [35] and [36]. Many prognostic gene-expression signatures have been developed and identified breast cancer subtypes that share the same biological features, mainly based on estrogen receptor, HER-2 and proliferation index[37]. The major five subtypes are luminal A, luminal B, HER2-enriched, basal-like and claudin low. Interestingly enough, it has been shown that the IGF-1R expression varies among breast cancer subtypes and moreover this is correlated with either good (e.g. luminal cancers) or bad prognosis (e.g. HER2-enriched tumors) [38] and [39]. Moreover, IGF-dependent enhanced cellular proliferation has been documented in triple negative breast carcinomas, which represent about 15% of breast carcinomas and are characterized by dismal clinical prognosis and limited so far therapeutic options [40]. Although receptor activation has been observed, neither mutations nor amplification of the gene that encodes IGF-1R have been described. However, it has been shown that certain IGF-1R single nucleotide polymorphisms (SNPs) might be useful predictive factors regarding recurrence of estrogen receptor positive breast cancer patients treated with endocrine agents [41].

4. Strategies targeting the IGF-related pathway

Several strategies have been developed and are being tested for therapeutic modulation of the IGF pathway. Reduction of IGF levels can be achieved through inhibition of the GH-releasing hormone (GHRH)–GH axis with either GHRH antagonists or GH antagonists [42]. In this vein, somatostatin analogues (e.g. octreotide) was evaluated in combination with tamoxifen as a treatment strategy in metastatic breast cancer patients with promising results, although a randomized clinical trial was terminated early due to low accrual rate [43]. Additionally, a randomized clinical trial with the same combination regimen in the adjuvant setting of postmenopausal early stage breast cancer patients showed no added clinical benefit of octreotide in tamoxifen [44].

Another approach is the neutralization of the ligands. This could be achieved with the use of IGFBPs. There has been some proof that IGFBP-1 could be employed as a therapeutic agent in breast cancer therapy [45]. Antibodies against IGF-1 and IGF-2 might also be used for the neutralization of these ligands and thus inhibition of the IGF axis [46]. Finally, truncated IGF-1R mutants that are soluble and bind circulating ligands have been reported as a potential mechanism to impair the IGF pathway [47]. Another therapeutic approach is to hinder the receptor activation. Two different strategies have been developed for the inhibition of IGF-1R; either monoclonal antibodies (mAbs) against the receptor or small molecules that inhibit the TK activity of IGF-1R and/or other receptors (e.g. IRs). Another approach is the use of antisense oligonucleotides complementary to the IGF-1R mRNA region that contains the translational start site [48] and [49]. From all the aforementioned strategies only mAbs against the extracellular part of the receptor and TK inhibitors are in an advanced stage of clinical development and will be further discussed.

4.1. MAbs against IGF-1R

One of the predominant strategies to block IGF pathway is the use of mAbs against the extracellular part of the receptor that hinder ligand binding and enhance down-regulation of the receptor. Several different antibodies have been produced and are in different phases of clinical development (Table 2).

Table 2. Strategies targeting IGF/IGFR pathway in breast cancer patients.

Agent	Class	Phase of development
Cixutumumab (IMC-A12) [50], [51] and [52]	Fully human IgG1 mAb against IGF-1R	II
Ganitumab AMG-479 [53] and [54]	Fully human mAb against IGF-1R	II
Figitumumab (CP-751-871) [55],[56] and [57]	Fully human IgG2 mAb against IGF-1R	I
Dalotuzumab (MK-0646) [58] and [59]	Humanized IgG1 mAb against IGF-1R and IGF-2R	II
MEDI-573 [60]	Fully human mAb that neutralizes IGF-I/IGF-II	I/II
BMS-754807 [62], [63], [64] and [65]	Dual IGF-1R/IR TKI	II
OSI-906 [66]	Dual IGF-1R/IR TKI	II

mAb, monoclonal antibody; TKI, tyrosine kinase inhibitor.

Table options

4.1.1. Cixutumumab (IMC-A12)

IMC-A12 is a mAb, fully human, against IGF-1R that inhibits ligand-dependent receptor activation [50]. In phase I testing cixutumumab exhibited a mild toxicity profile with hyperglycemia reported as the most frequent adverse event. Other adverse events were pruritus, rash, anemia, psoriasis and infusion-related reaction [51]. Cixutumumab has been tested in the context of a randomized phase II study in patients with advanced or metastatic HER2+ breast cancer treated previously with trastuzumab and anthracycline and/or taxanes [52]. Patients were randomly allocated in a 2:1 ratio to either capecitabine, lapatinib with or without cixutumumab 6 mg/kg intravenously on days 1, 8, 15 (NCT00684983). Another phase II trial of cixutumumab in combination with temsirolimus, in patients with locally recurrent or metastatic breast cancer who have failed first line treatment, is currently recruiting patients (NCT00699491).

4.1.2. Ganitumab (AMG-479)

AMG-479 is a fully-human mAb against IGF-1R that also inhibits ligand depend receptor activation. In phase I testing, the most common grades 1–2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia [53]. AMG-479 has been tested in the context of a randomized phase II study in 156 postmenopausal women with hormone receptor positive metastatic or locally advanced breast cancer who had documented disease progression on prior endocrine treatment [54]. Patients were randomized to intravenous administration of 12 mg/kg AMG-479 every two weeks plus placebo or an endocrine agent (exemestane or fulvestrant). Median progression-free survival was 3.9 months (range, 36–5.3 months) in the AMG-479 only arm compared with 5.7 months (range, 4.4–7.4 months; P = 0.435) in the combinatorial arm. A phase I/II trial of trastuzumab in combination with AMG-479 in HER-2 over-expressing metastatic breast cancer patients progressing on trastuzumab- or lapatinib-based therapy will also begin recruitment in the mid of 2012 (NCT01479179).

4.1.3. Figitumumab (CP-751-871)

Figitumumab is a fully humanized IgG2 mAb against IGF-1R. Its recommended dose is 20 mg/kg repeated weekly. In phase I trials treatment-related toxicities were generally mild. The most common adverse events reported were hyperglycemia, anorexia, nausea, elevation of liver function tests, diarrhea, hyperuracemia and fatigue [55]. Figitumumab had shown significant activity against non-small-cell lung cancer (NSCLC) and it was planned to be evaluated in combination with chemotherapy in a randomized phase III trial in patients with metastatic NSCLC [56]. However, the study was early discontinued on December 2009 because an independent monitoring committee concluded that the combination of figitumumab plus chemotherapy would be unlikely to meet the primary endpoint of improving overall survival compared to chemotherapy alone. Additionally, there were also some concerns that hyperglycemia could be a potential contributor of increased patients’ morbidity. In regard to breast cancer, figitumumab was planned to be tested in phase I trials as neo-adjuvant treatment, but the trial was withdrawn prior initiation, although there are preclinical data showing a additive and/or synergistic effect of figitumumab with chemotherapy in basal breast cancer subtype [57].

4.1.4. Dalotuzumab (MK-0646)

Dalotuzumab is a humanized IgG1 mAb that blocks both IGF-1R and IGF-2R, while it does not block IR [58]. Furthermore, dalotuzumab has been demonstrated to elicit antibody-dependent cellular cytotoxicity. In phase I trials dalotuzumab has displayed a favorable toxicity profile with hyperglycemia reported as the most frequent adverse event. Other toxicities included chills, nausea, rash, asthenia and pyrexia, while one patient developed grade III purpura [59]. A proof-of-principle clinical trial has recently completed accrual in patients with operable stage I–IIIa breast cancer (NCT00759785). Further clinical testing is also ongoing (NCT01234857).

4.1.5. MEDI-573

Medi-573 is a fully-humanized mAb that neutralizes both IGF-I and IGF-II and has been shown in vitro and in vivo to inhibit IGF-signaling through both IGF-1R and IR-A [60]. A phase I/II multicenter trial is currently recruiting patients with hormone receptor positive and HER-2 negative metastatic breast cancer in order to assess the safety and anti-tumor activity of MEDI-573 in combination with an aromatase inhibitor (NCT01446159).

4.2. IGF-1R small molecule inhibitors

Most of currently developing molecules that target the TK domain of IGF-1R have dual action on both IGF-1R and IR (Table 2). Additionally many chemical compounds that are competitive inhibitors of ATP binding on the TK domain of these receptors are tested [61].

4.2.1. BMS-754807

BMS-754807 is an oral dual IGF-1R/IR TKI. Preclinical data have shown synergistic in vitro anti-proliferative activity when it is combined with any kind of endocrine therapy (tamoxifen, aromatase inhibitors, fulvestrant) in hormone-sensitive breast carcinomas [62] and [63]. In treatment-naïve breast carcinomas and in tamoxifen- or letrozole-resistant tumors, the combination of letrozole with BMS-754807 induced significant tumor regression in vivo, which was not observed with an anti-IGF-1R mAb. The lack of activity of the IGF-1R specific antibody and IR isoform expression analyses suggested that IR-isoform A blockade was important for this synergistic action. All these data were the basis for the initiation of a phase II clinical trial in patients with locally advanced/metastatic, estrogen-receptor positive, non-steroidal aromatase inhibitor resistant breast carcinomas (NCT01225172). In this trial the combination of BMS-754807 and letrozole versus the investigational agent only was evaluated with primary endpoint being 6-month progressive-free survival [64]. Additionally, there are preclinical data suggesting that BMS-754807 in combination with chemotherapy might exhibit strong anti-tumor effect in triple negative breast carcinomas [65].

4.2.2. Linsitinib (OSI-906)

OSI-906 is an oral TKI that selectively inhibits autophosphorylation of both human IGF-1R and IR. Combined treatment with OSI-906 and fulvestrant has been shown to prevent the emergence of hormone-resistant breast cancer cells in vitro and in vivo [66]. A phase II study has been planned evaluating the combination of endocrine treatment, OSI-906 with or without erlotinib (EGFR-TKI) in patients with hormone-responsive metastatic breast cancer (NCT01205685).

5. The IGF-related pathway and its role in mediating resistance to anticancer therapies

Although significant improvement has been achieved and more effective agents are currently available in our treatment arsenal against metastatic breast cancer, the vast majority of patients will develop resistance. The IGF pathway has been reported to play an important role in the development of resistance against several DNA-damaging agents. IGF protects cancer cells from apoptotic cell death via IGF-1R-mediated activation of the PI-3K/AKT pathway, as well as rescue from drug-induced cytostasis through activation of MAPK pathway signals [67] and [68]. The IGF system transduces signals that may also confer a multidrug resistance (MDR) phenotype to cancer cells, by the induction of MDR-related genes such as Mdr-1 (with increased expression of its product, the p-glycoprotein drug efflux pump) and the manganese superoxide dismutase (MnSOD) [69]. Indeed, IGF-1R signaling has been associated with resistance and increased survival of breast cancer cells treated with 5-fluorouracil, methotrexate, or camptothecin via IGF-1R inhibition of apoptosis [29] and [70]. Inhibition of IGF with the use of mAbs or TKIs results in enhancement of the cytotoxic effect of several chemotherapy agents including gemcitabine, irinotecan, etoposide, carboplatin, adriamycin, ifosfamide, navelbine, 5-fluorouracil and vincristine, both in vitro and in vivo [71].

Moreover, resistance to hormonal therapy against breast cancer may be partially explained by cross-talk between ER and IGF pathways [66] as well as through the modulation of downstream pathways [72] (Fig. 2). One possible mechanism by which breast cancer cells escape tamoxifen-induced apoptosis may be the activation of the AKT pathway via IGF-mediated signaling, which leads to phosphorylation of ER at Ser-167 and subsequent ligand-independent activation of ER [73]. IRS-1 is the major adaptor protein of IGF-1R/IRs but also the mediator of cross-reaction with other membrane-associated molecular networks that are responsible for the development of hormone-resistance in breast carcinomas [74]. The synergism of combined targeting of ERs and IGF pathway has been shown in vitro [75]. Additionally, expression levels of IGFBPs were found to be predictive factors for response to hormonal agents. For example, IGFBP-2 mRNA and protein levels have been reported to be over-expressed in cell lines resistant to the anti-estrogens fulvestrant and tamoxifen [76].

Fig. 2. Cross-talk between ER- and IGF-related signaling cascades. AP-1, activator protein-1; BTM, basal transcriptional machinery; ER, estrogen receptor; EREs, estrogen response elements; Grb2, growth factor receptor-binding protein 2; HAT, histone acetyltransferase; HDAC, histone deacetylase; Hsp90, heat-shock protein 90; IGF, insulin-like growth factor; IGF-1R, IGF-1 receptor; IGFBPs, IGF-binding proteins; IRS-1, insulin receptor substrate-1; MAPK, mitogen-activated protein kinase; MEK, MAPK/extracellular signal-regulated kinase (ERK) kinase; mTOR, mammalian target of rapamycin; P, phosphate groups; PI-3K, phosphatidylinositol-3 kinase; PTEN, phosphatase and tensin homologue deleted on chromosome 10; Sos, son of sevenless; TREs, 12-O-tetradecanoylphorbol-13-acetate (TPA) response elements.

Figure options

The IGF-1R pathway has also been implicated in resistance to radiotherapy (RT). It is believed that it exerts its activity, in part, by modulating ataxia telangiectasia mutated (ATM) function, which controls the response of the cell to DNA damages induced by RT via triggering cell-cycle arrest and apoptosis as well as DNA repair [77]. Moreover, it has been documented that inhibition of IGF-1R signaling enhances sensitivity of breast cancer to RT [78] and [79], and thus it might represent a way to enhance the efficacy of RT in cases of radioresistant tumors.

6. The IGF-related pathway and other targeted treatments

IGF-1R plays an important role in the development of resistance to the anti-HER-2 mAb trastuzumab, via the formation of heterodimers with the ERBB2 receptor [80]. Lu et al. have demonstrated that trastuzumab was able to inhibit the growth of MCF-7/HER2-18 cells, which over-express ERBB2 receptors and express IGF-1R, only when IGF-1R signaling was minimized [81]. In a similar manner, Chakraborty et al. [82] showed that when treating breast cancer cell lines with either ERBB2 or IGF-1R antagonists no single receptor-targeting drug was capable of inducing apoptosis, but combining antagonists of both receptors induced a dramatic degree of apoptosis in both cell lines. Therefore, combination of these two drug classes could be a way to improve results in tumors whereby the single agent produces minimal anti-neoplastic effect [83]. Although IGF-1R expression has not been shown to represent a predictive factor [84], expression levels of IGFBPs might represent potential useful predictive markers of trastuzumab activity [85].

IGF-1R inhibition may also enhance the efficacy of inhibitors of other kinases, such as mammalian target of rapamycin (mTOR). In patients treated with mTOR inhibitors such as rapamycin, temsirolimus and everolimus, an up-regulated IGF-1R-mediated signaling leads to induction of PI-3K/AKT phosphorylation, an important antiapoptotic cascade [86] and [87], although some reports suggest that this diminished effectiveness of mTOR inhibitors is independent of IGF-1R [88]. This combination might be very useful in the light of the recent positive clinical results of mTOR inhibitors in patients with advanced breast cancer [13].

7. Concluding remarks

The IGF pathway has a well-documented role in the malignant transformation of normal breast epithelium. There is sufficient evidence implicating this network in the development and/or progression of breast carcinomas. Given the fact that IGF pathway is expressed in several other normal tissues it was anticipated that the disruption of this pathway could potentially lead to several toxicities. However, data from several clinical studies reported during the last years have shown a very favorable toxicity profile with the majority of adverse events being mild [89]. The most frequently reported toxicity across all studies was hyperglycemia. However, in most cases it was mild, tolerable, reversible and easily managed with oral hypoglycemic drugs[59]. It should be noted that breast cancer patients with diabetes were excluded from these trials and that patients with concomitant treatment with corticosteroids were more susceptible to develop hyperglycemia[89]. Although the mechanism of this toxicity is not quite clear, it is believed that inhibition of the IGF pathway leads to a feedback increase of the circulating levels of GH. These elevated levels of GH result to enhancement of the neoglycogenic effect and insulin resistance thus resulting in hyperglycemia [90]. Hematological toxicity has also been reported (anemia, lymphopenia, thrombocytopenia), while other common toxicities are fatigue and mild skin toxicities (pruritus, rash).

Collectively, many research efforts have identified an extensive signal transduction network responsible for the biological actions of IGF. Several strategies have been investigated and are currently evaluated to inhibit IGF signalling circuits. Resistance to anti-IGF agents has been also associated with several components of IGF axis. Huang et al. demonstrated that cell lines sensitive to IGF-1R inhibitors over-express IGF-1, IGF-2, and IGF-1R [91]. IGF-1 and IGF-2 together were able to predict sensitivity of several different cell lines to BMS-536924 more efficiently than either ligand alone. These observations suggest that sensitive cell lines may have enhanced activity of IGF-1R pathways, and that IGF-1R pathway is likely to play a major role in the growth process of these cell lines. Thus, gathered preclinical and clinical data has implicated the IGFs in breast cancer biology and were the basis for the development of treatment strategies for use in breast cancer patients. However, several caveats have aroused. For example, much scientific effort is focused in the identification of predictive markers. In this vein, it has been reported that expression of IR may play a role in the insensitivity to IGF-1R inhibition in human breast cancer cells [92]. Ulanet et al. demonstrated that IGF signaling was significantly inhibited in cell lines with high IGF-1R to IR expression ratios, whereas this was not the case in cells lines characterized by low IGF-1R to IR ratios [92]. Furthermore, they demonstrated that knockdown of IR expression markedly sensitized resistant cell lines. Additionally, there are data showing that in tamoxifen-resistant breast cancer cells IGF-1R kinase inhibitors are more effective by inhibiting both IGF-1R and IR signaling cascades [93]. Moreover, IR isoform expression might be important predictive factor regarding the activity of IGF inhibitors [94]. IGFBPs might be also useful to predict sensitivity of breast carcinomas in IGF-1R targeting [95]. However, the identification of a concrete and easily reproducible predictive marker of targeting IGF/IGF-1R axis is still under development.

The role of various IGF receptor isoforms as well as the contribution of hybrid receptors to breast cancer still represents a major drawback in more effective targeting of IGF/IGF-1R pathway for therapeutic purposes in breast cancer patients. As co-targeting of IGF1R and IRs moves forward in clinical development, evaluating IRs levels in clinical tumor samples becomes critical for identifying the most appropriate population to receive anti-IGF agents. Moreover, IR subtypes have previously been shown to differ regarding the proliferation index, response to hormonal therapy and overall clinical outcome of breast carcinomas. Therefore, the association of the IRs ratio with a particular breast cancer subtype may identify patients more likely to respond to IGF-targeted therapy in combination with currently used treatment options.

Conflict of interest

The authors declare no conflict of interest.

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乳腺癌治疗中胰岛素样生长因子的靶向治疗的应用

Targeting insulin-like growth factor in breast cancer therapeutics

Abstract

Keywords

1. Introduction