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The Oncologist, Vol. 13, No. 1, 16-24, January 2008; doi:10.1634/theoncologist.2007-0199
© 2008 AlphaMed Press

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Clinical Pharmacology

The Emerging Role of the Insulin-Like Growth Factor Pathway as a Therapeutic Target in Cancer

Paula D. Ryan, Paul E. Goss

Massachusetts General Hospital, Boston, Massachusetts, USA

Key Words. Insulin-like growth factor-I • Insulin-like growth factor-II • Insulin-like growth factor-I receptor Breast cancer • Review

Correspondence: Paula D. Ryan, M.D., Ph.D., Massachusetts General Hospital, LRH 308, 55 Fruit Street, Boston, Massachusetts 02114, USA. Telephone: 617-726-5046; Fax: 617-643-0589; e-mail: pdryan{at}partners.org

Received October 18, 2007; accepted for publication December 3, 2007.

Disclosure: P.E.G. has acted as a consultant to Novartis, AstraZeneca, and Pfizer, and P.D.R. has acted as a consultant to Pfizer, Genentech, and Novartis. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   Learning Objectives
Top
 Footnotes
 Learning Objectives
Abstract
 Introduction
 The IGF System
 Evidence for the Role...
 Strategies for Targeting the...
 Ongoing Clinical Trials
 Future Directions
 References
 
After completing this course, the reader will be able to:

  1. Discuss the characteristics of the IGF system including its endocrine as well as tissue growth factor properties.
  2. Discuss the preclinical background and the rationale for targeting the IGF system in cancer therapy.
  3. Discuss ongoing phase I and phase II clinical trials targeting the IGF-IR in solid tumor malignancies.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Footnotes
 Learning Objectives
 Abstract
Introduction
 The IGF System
 Evidence for the Role...
 Strategies for Targeting the...
 Ongoing Clinical Trials
 Future Directions
 References
 
The insulin-like growth factor signaling pathway is important in many human cancers based on data from experimental models as well as epidemiological studies. Important therapies targeted at this pathway have been or are being developed, including monoclonal antibodies to the insulin-like growth factor-I receptor and small molecule inhibitors of the tyrosine kinase function of this receptor. These investigational therapies are now being studied in clinical trials. Emerging data from phase I trials are encouraging regarding the safety of the monoclonal antibodies. In this manuscript, the rationale for targeting the insulin-like growth factor system is reviewed in addition to a summary of the available clinical trial data.


   INTRODUCTION
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
The IGF System
 Evidence for the Role...
 Strategies for Targeting the...
 Ongoing Clinical Trials
 Future Directions
 References
 
The insulin-like growth factor (IGF) signaling system plays a key role in the growth and development of many normal tissues and regulates overall growth of organisms. The insulin-like growth factor I receptor (IGF-IR) is a receptor tyrosine kinase that serves as a key positive regulator of the IGF-I system [1]. Serum IGF-I levels increase during puberty as pituitary-derived growth hormone (GH) increases liver IGF-I expression. Children with mutations in both IGF-I and IGF-IR have been described as having poor in utero and postnatal growth, microcephaly, and neurodevelopmental delay [2, 3]. IGFs play an important role throughout life in neuronal survival [4, 5], and the IGF-IR has been shown to play an important role in cardiac myocyte survival [6].

In response to the stimulatory ligands IGF-I and IGF-II, IGF-IR signaling results in both proliferative and antiapoptotic effects [7]. Data from experimental models and population studies have implicated the IGF-I system in the pathogenesis of many different human cancers, including breast, prostate, lung, and colon cancer [8–13]. There are also several lines of evidence that dysregulation of the IGF-I system and enhanced IGF-IR activation are involved in resistance to certain anticancer therapies, including cytotoxic chemotherapy, hormonal agents, biological therapies, and radiation [14–22]. Thus, by blocking prosurvival signaling in this pathway, inhibition of IGF-IR should also enhance the activities of these agents. Indeed, drugs that target the IGF-IR have now been developed and we are beginning to see results emerging from clinical trials with these agents. In this manuscript we review the rationale for targeting the IGF-IR system in human cancer as well as review drugs in development targeting this system and the clinical trials that are now under way with some of these agents.


   THE IGF SYSTEM
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 The IGF System
Evidence for the Role...
 Strategies for Targeting the...
 Ongoing Clinical Trials
 Future Directions
 References
 
The complex IGF system includes key molecules that operate both at the level of the whole organism and at a cellular level [23–26]. IGF has characteristics of both a circulating hormone and a tissue growth factor. Most circulating IGFs are produced in the liver and are subject to both hormonal and nutritional factors. GH, which is produced in the pituitary gland under the control of the hypothalamic factors growth hormone–releasing hormone and somatostatin, stimulates IGF-I production. Malnutrition is known to reduce this stimulatory function. The IGF binding proteins (IGFBPs) are also produced in the liver. The ligands IGF-I and IGF-II as well as the IGFBPs are delivered in an endocrine manner through the circulation from the liver to act in IGF-responsive tissues. IGFs and IGFBPs are also synthesized in other organs where autocrine or paracrine mechanisms take place, often involving interactions between stromal and epithelial cell populations [27] (Fig. 1).


Figure 1
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  		Figure 1. Growth hormone (GH) is produced in the pituitary gland under the control of the hypothalamic factors, growth-hormone-releasing-hormone (GHRH) and somatostatin (SMS). GH is the key stimulator of insulin-like growth factor (IGF) production in the liver. IGF binding proteins (IGFBPs) are also produced in the liver, but IGFs can also be produced locally through autocrine or paracrine mechanisms.

 
There are three ligands: IGF-I, IGF-II, and insulin itself. These ligands interact with at least four receptors: the type I IGF receptor (IGF-IR), the type II IGF receptor (IGF-IIR), the insulin receptor (IR), and hybrid receptors of IGF and insulin (Fig. 2). Because of its twofold higher affinity for the IGF-IR than for the IR, most of the effects of IGF-I result from activation of the IGF-IR. IGF-IR–IR hybrid receptors retain high affinity for IGF-I, but have a lower affinity for insulin. The IGF system also consists of six binding proteins (IGFBPs) that regulate IGF action [28]. The IGFBPs and IGFBP proteases play a key role in regulating ligand bioavailability, among other actions that are under investigation [29]. IGFBPs in extracellular fluid modulate interactions between IGF ligands and IGF receptors; their affinity for IGF-I and IGF-II is about the same as that of IGF-IR. Under different physiological conditions, the IGFBPs can either increase or decrease IGF signaling, probably related to the fact that IGFBPs can prolong the half-lives of IGFs but also can compete with receptors for free IGF-I and IGF-II. IGF-I and IGF-II are ligands for the IGF-IR, which is a transmembrane tyrosine kinase composed of two {alpha} and two β subunits closely related to the IR and widely expressed in human tissues. Binding of the ligands induces conformational changes in the IGF-IR and activation of its intrinsic tyrosine kinase activity. Once phosphorylated, the intracellular portion of the receptor serves as a docking site for several receptor substrates, including insulin receptor substrate (IRS)-1 to IRS-4 and SRC homology and collagen (Shc) [30, 31]. These substrates then initiate the phosphorylation cascades that transmit the IGF-IR signal.


Figure 2
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  		Figure 2. The insulin-like growth factor (IGF) system consists of the ligands, cell surface receptors, and the IGF binding proteins (IGFBPs). The insulin-like growth factor receptor (IGF-IR) is a tyrosine kinase cell-surface receptor that binds either IGF-I or IGF-II. The IGFBPs have key roles in regulating ligand bioavailability. IGF-II interacts with IGF-IR, IGF-IIR (lacks tyrosine kinase domain), the exon 11-lacking (A) form of the insulin receptor (IR) and the IGFBPs. Hybrid receptors form from dimerization of IGF-IR and IR hemireceptors. These hybrid receptors retain high affinity for IGF-I, but have a significantly reduced affinity for insulin.

 
Two different antiapoptotic signaling pathways have been identified for the IGF-IR. Phosphorylated IRS-1 can activate phosphatidylinositol 3' kinase, leading to activation of protein kinase B (Akt), among other downstream substrates [32]. Akt activation enhances protein synthesis via mammalian target of rapamycin (mTOR) activation and signals the antiapoptotic effects of the IGF-IR through phosphorylation and inactivation of B-cell chronic lymphocytic leukemia/lymphoma 2 antagonist of cell death (Bad) [33]. Also, recruitment of growth factor receptor-bound protein-2/son of sevenless (Grb2/SOS) by phosphorylated IRS-1 or Shc leads to recruitment of Ras and activation of the Raf-1/mitogen-activated protein kinase (MAPK)–extracellular signal–related kinase (ERK) kinase/ERK pathway and downstream nuclear factors, resulting in induction of cellular proliferation [34, 35] (Fig. 3).


Figure 3
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  		Figure 3. Binding of the ligands insulin-like growth factor I (IGF-I) and insulin-like growth factor II (IGF-II) to insulin-like growth factor receptor (IGF-IR) activates its intrinsic tyrosine kinase activity resulting in signaling through cellular pathways that stimulates proliferation and inhibits apoptosis. The key downstream signaling pathways include PI3K-AKT-TOR and the RAF-MEK-ERK pathway. Therapeutic approaches that target the IGF-IR are being tested clinically and include antibodies directed at the extracellular portion of the receptor and small molecule tyrosine kinase inhibitors with specificity for IGF-IR.

Abbreviations: ERK, extracellular signal–related kinase; IGF, insulin-like growth factor; IGF-IR, IGF-I receptor; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase; MEK, MAPK–ERK kinase; PI3K, phosphatidylinositol 3' kinase; mammalian TOR, target of rapamycin.

 

   EVIDENCE FOR THE ROLE OF IGF IN HUMAN MALIGNANCY
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 The IGF System
 Evidence for the Role...
Strategies for Targeting the...
 Ongoing Clinical Trials
 Future Directions
 References
 
The IGF system plays a critical role in normal growth and development in humans and animals. During puberty, elevated sex steroid levels stimulate GH production, leading to increases in liver IGF-I expression and serum IGF-I levels [36]. In animal models, disruption of the IGF-IR signaling pathway results in reduced breast and prostate growth, suggesting that IGF-IR is involved in normal organogenesis [37, 38]. Although serum IGF-I levels decline progressively after puberty, significant levels of IGF-II are detectable throughout adulthood. IGF-IR mRNA levels also decline after puberty but remain high in the brain and in the kidney. However, increased expression of IGF-I and IGF-II has been documented in various human cancers, one line of evidence that the IGF system may be involved in tumor growth [1]. Taken together it appears that the IGFs play a paracrine or autocrine role in promoting tumor growth in situ during tumor progression, depending on the tissue of origin.

Epidemiological studies also provide evidence for a role of IGFs in tumor development. Elevated plasma concentrations of IGF-I (or IGFBP-3) have been linked to a higher risk for several cancers, with the most compelling data seen in large prospective studies of breast, colon, prostate, and lung cancer [11, 39–41] (Table 1). Although IGF-IR mutations have not been described in tumors, several genetic polymorphisms in genes encoding IGF-I or IGFBP-3 have been reported, and may be important in the risk for breast cancer, lung cancer, colorectal cancer, and prostate cancer [42–47]. For example, a known genetic cytosine-adenine (CA) repeat polymorphism in the promoter region of the human IGF-I gene may be associated with changes in the levels of circulating IGF-I. The 19-CA-repeat allele was more frequent in patients with prostate cancer than in controls, and was shown to be a novel predictor in prostate cancer patients with bone metastases [48, 49].


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  		Table 1. Selected population studies of serum insulin-like growth factor (IGF)-I levels and cancer risk

 
There is strong evidence that the IGF-IR pathway is important in promoting oncogenic transformation, growth, and the survival of cancer cells. Many IGF-IR–positive cancer cells are stimulated by IGF-I. Both experimental and clinical studies have demonstrated that IGF-IR is overexpressed in cancer cells compared with normal tissues [50, 51] and that IGF-IR is ubiquitously expressed in cancer tissues [51, 52]. For example, in one study, IGF-IR overexpression was found in 43.8% of breast tumors [53], and in another study, of 136 breast cancer samples, 39% were IGF-IR positive and expression of IGF-IR correlated with estrogen receptor (ER) status and disease-free survival [54]. The IGF-IR has also been shown to be crucial for the unique malignant property of anchorage-independent growth, and the degree of anchorage independency reflects the extent of malignancy [23]. There is mounting evidence from in vitro studies that IGF-IR signaling influences other growth factors or receptors such as vascular endothelial growth factor and the epidermal growth factor receptor (EGFR) [55].

Animal models have also provided evidence that IGF plays a role in cancer initiation, progression, and metastasis. In the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, selective overexpression of human IGF-I DNA in basal epithelial cells of the prostate results in overexpression of IGF-IR in these cells and spontaneous development of prostate cancer [56]. Noble rats exposed to 1 year of testosterone and estradiol demonstrated a stepwise progression from hyperplasia to dysplasia to carcinoma in situ and adenocarcinoma of the prostate [57]. In another mouse model, interaction between mutant p53 and IGF-I accelerated mammary tumor production [58], and the engineering of mice with a novel CD8-{alpha}–IGF-IR fusion protein under the control of the mouse mammary tumor virus promoter led to constitutive activation of the IGF-IR and the animals developed salivary and mammary adenocarcinomas as early as 6 weeks after birth and a palpable mammary mass at 8 weeks of age [59].


   STRATEGIES FOR TARGETING THE IGF SYSTEM
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 The IGF System
 Evidence for the Role...
 Strategies for Targeting the...
Ongoing Clinical Trials
 Future Directions
 References
 
Lowering IGF-I Concentrations
One potential way to block the IGF pathway is to lower ligand concentrations. This could be achieved by blocking the release of GH from the pituitary gland, which in turn results in lower serum IGF-I levels. Thus, in prostate cancer models, GH-releasing hormone antagonists have been demonstrated to have antitumor activity [60]. Also, pegvisomant, a pegylated mutant GH, has been developed and approved for the treatment of acromegaly, a condition of GH excess. This compound has antitumor activity in human meningiomas in nude mice [61]. Another strategy that has potential to block both IGF-I as well as IGF-II involves neutralizing monoclonal antibodies and IGFBPs, as demonstrated in breast cancer [62] and prostate cancer [63] models.

Targeting IGF-IR
The emphasis of drug development targeting the IGF pathway has been directed at the IGF-IR, with antireceptor antibodies and tyrosine kinase inhibitors emerging in clinical trial design. Several monoclonal antibodies that block ligand binding and downregulate the IGF-IR have been developed [13, 64–68]. Downregulation of the receptor appears to be the most important mechanism of action; a single-chain antibody directed against the IGF-IR acts as a full agonist of the receptor yet retains its ability to downregulate receptor levels over time and inhibit tumor growth [13, 64]. None of the antibodies developed have crossreactivity with the IR and should not disrupt insulin interaction with its receptor. Monoclonal antibodies to the IGF-IR are now in phase I and phase II development in the treatment of several solid tumors (Table 2). Several tyrosine kinase inhibitors have also been developed [59, 69, 70]. These molecules have a higher affinity for the IGF-IR than the IR; however, there is still likely to be some crossinhibition as a result of the high degree of homology between the tyrosine kinase domains of the two receptors. Also, tyrosine kinase inhibitors have not been reported to downregulate IGF-IR levels. Compounds with this mechanism of action are in preclinical laboratory testing and phase I clinical development (Table 2).


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  		Table 2. Compounds that target the insulin-like growth factor I receptor in clinical development

 
A large body of in vitro laboratory evidence demonstrates that IGF-IR inhibition may be particularly useful in overcoming resistance to other targeted therapies including the EGFR, human epidermal growth factor receptor 2, mTOR, and breakpoint cluster region–Abelson (BCR-ABL) [55], thus suggesting that inhibition of the IGF-IR may be particularly useful in combination with other anticancer therapies.


   ONGOING CLINICAL TRIALS
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 The IGF System
 Evidence for the Role...
 Strategies for Targeting the...
 Ongoing Clinical Trials
Future Directions
 References
 
A phase I dose escalation study of the anti–IGF-IR monoclonal antibody CP-751,871 in patients with solid refractory tumors was presented at the American Society of Clinical Oncology (ASCO) meeting in 2007 [71]. This antibody is a potent fully human IgG2 monoclonal antibody antagonist of the IGF-IR. CP-751,871 antagonized the binding of IGF-I to IGF-IR and IGF-IR phosphorylation and induced downregulation of IGF-IR in vitro and in vivo in tumor xenograft models in a dose-dependent manner [72]. CP-751,871 also blocks IGF-I – and IGF-II–mediated phosphorylation of IGF-IR and Akt, suggesting both activating ligands are antagonized. In addition to exhibiting single-agent activity in vivo, CP-751,871 also enhanced the activity of cytotoxic chemotherapy and tamoxifen in tumor xenografts [72].

In a phase I study, CP-751,871 was administered i.v. every 3 weeks in patients with advanced solid tumors. Overall, CP-751,871 was found to have a favorable safety profile among 24 enrolled patients; the maximum tolerated dose (MTD) was not identified because it exceeded the maximum feasible dose of 20 mg/kg. The overall median number of treatment cycles delivered was 4.3, ranging from 1 to 20 cycles. There were no treatment-related toxicities of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade >3 reported during the study. The most common adverse effects were hyperglycemia, anorexia, nausea, elevated aspartate aminotransferase, and elevated gammaglutamyltransferase. Plasma concentrations of CP-751,871 increased in a dose-dependent manner and a moderate accumulation in the plasma was observed in most patients, with a mean accumulation ratio of 2.1 at 20 mg/kg. At the 20-mg/kg dose, 10 of 15 patients experienced stability of disease, of whom two achieved long-term disease stability. Among all 24 patients, no confirmed tumor responses, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST), were observed; however, one patient with metastatic thymoma experienced an approximate 10% reduction in tumor size by the RECIST and has had prolonged disease stability for >1 year.

A phase II randomized, noncomparative study of CP-751,871 in combination with paclitaxel and carboplatin (designated TCI) as first-line therapy for non-small cell lung cancer (NSCLC) was also presented at the ASCO meeting in 2007 [73]. It has been previously shown that transgenic overexpression of IGF-I induced spontaneous lung tumors in mice [74]. IGF-IR activation was seen in human NSCLC cells [75] and lower IGFBP-3 expression was associated with poor prognosis in stage I resected NSCLC patients [9, 76, 77]. This study involved randomization of patients to either paclitaxel (T), 200 mg/m2, carboplatin (C), area under the concentration–time curve of 6, and CP-751,871 (I), 10 mg/kg, or TC alone every 3 weeks. Hyperglycemia and dehydration were the most common adverse events and were managed with standard diabetic therapy. Analysis of 73 patients enrolled revealed objective responses in 22/48 (46%) patients receiving TCI versus 8/25 (32%) patients receiving TC, warranting further investigation (71% of responses in squamous histology patients). Additional patients are currently being enrolled.

A phase I study of AMG 479, a high-affinity fully humanized monoclonal antibody against IGF-IR, in patients with advanced solid tumors found this antibody to be well tolerated at doses up to 20 mg/kg i.v. every 2 weeks [78]. Thrombocytopenia (NCI CTCAE grade ≥3) was observed in four patients and grade 3 transaminitis was observed in one patient. Evidence of antitumor activity was notable with one complete response in a patient with Ewing's sarcoma, and one partial and one mixed response in patients with neuroendocrine tumors. Based on these results, a phase I expansion study in Ewing's family of tumors and/or desmoplastic small round cell tumors is ongoing and phase Ib studies in combination with either panitumumab or gemcitabine are under way.

A phase I study, in 26 patients with refractory solid tumors, of R1507, a human monoclonal antibody to the IGF-IR, revealed treatment to be well tolerated, with no dose-limiting toxicities, and an MTD was not achieved [79] with the maximal dose of 16 mg/kg every 3 weeks. One patient had mild (grade 1) flushing starting 1 day after the R1507 infusion and subsiding within 24 hours. Analysis of the pharmacokinetic data supports weekly dosing of 9 mg/kg for future trials.

A first-in-human, phase I dose escalation study with weekly administration of IMC-A12 [80], a fully humanized monoclonal antibody to IGF-IR, showed that this agent was also well tolerated in 21 patients treated, but hyperglycemia was the most common toxicity (no grade >3). The MTD was not reached with the recommended weekly dose for phase II of 6 mg/kg. Preliminary evidence suggests clinical activity.

The potential metabolic effects of inhibiting the IGF-IR need to be carefully evaluated in clinical trials. As noted above, hyperglycemia has been seen thus far in phase I studies with monoclonal antibodies to the IGF-IR, yet, fortunately, the toxicity has generally been mild and easily managed, and based on pharmacokinetic parameters is unlikely to be a result of IR binding. The mechanism of the hyperglycemia is not completely understood, but data that link the IGF-I ligand system and glucose metabolism may provide clues to the metabolic effects of anti-IGF-IR therapy. IGF-I administration in humans results in hypoglycemia, decreased serum levels of fatty acids, and increased lipogenesis [81, 82]. Recombinant IGF increases insulin sensitivity in the liver and muscle in patients with type II diabetes mellitus and results in better glucose control [83]. IGF-I also suppresses hepatic, renal, and intestinal gluconeogenesis, and via the IGF-IR has effects that mimic insulin, including increased glycogen formation, increased translocation of glucose transporters, and increased glucose uptake [84, 85]. Genetic alterations that cause IGF-I or IGF-IR inactivation result in human GH accumulation [86], and it is possible that human GH may have hyperglycemic effects by promoting liver gluconeogenesis [87].


   FUTURE DIRECTIONS
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 The IGF System
 Evidence for the Role...
 Strategies for Targeting the...
 Ongoing Clinical Trials
 Future Directions
References
 
Targeted therapy to the IGF system is being studied in combination with chemotherapy as demonstrated by the phase II study in lung cancer described above. Other combination strategies are also being employed in breast cancer, given the important links between the ER and the IGF-IR pathway that have been discovered in experimental models. 17β-estradiol (E2) has been shown to stimulate activation of the IGF-IR pathway through its phosphorylation. Synergistic induction of cell proliferation and survival in breast cancer cells by interactions between the ER and IGF pathway has been demonstrated [88]. E2 induces the formation of a complex of the adaptor protein Shc, ER-{alpha}, and IGF-IR. Downregulation of Shc, ER-{alpha}, and IGF-IR with specific small inhibitory RNAs all blocked E2-induced MAPK phosphorylation, suggesting that Shc and IGF-IR may serve as key elements in the translocation of ER-{alpha} to the cell membrane [89]. The strategy of combining therapy that targets both the ER and IGF-IR is being employed in an ongoing phase II trial of CP-751,871 in combination with the aromatase inhibitor exemestane versus exemestane alone in postmenopausal patients with metastatic hormone receptor–positive breast cancer.

In summary, the IGF system is emerging as a promising new target in cancer therapy and promises to revolutionize the way we select therapies in combination with chemotherapy, endocrine therapy, and other biological agents.


   FOOTNOTES
 
Conception/design: Paula D. Ryan, Paul E. Goss

Administrative support: Paula D. Ryan

Collection/assembly of data: Paula D. Ryan

Manuscript writing: Paula D. Ryan, Paul E. Goss

Final approval of manuscript: Paul E. Goss


   REFERENCES
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 The IGF System
 Evidence for the Role...
 Strategies for Targeting the...
 Ongoing Clinical Trials
 Future Directions
 References
 

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