Targeting the insulin-like growth factor receptor pathway in lung cancer: problems and pitfalls

Abstract

The insulin-like growth factor (IGF) pathway is a complex pathway involving interactions between membrane-bound receptors, ligands, binding proteins, downstream effectors, and other receptor tyrosine kinase signaling cascades. The IGF pathway has been identified as a potential therapeutic target in non-small cell lung cancer (NSCLC) based on the following provocative factors. Preclinical observations in NSCLC have shown that this pathway is involved in tumor cell proliferation, survival, and invasiveness. In addition, IGF-1R protein expression is found in a significant number of non-small cell tumor specimens. Initial therapeutic efforts involved the development of monoclonal antibodies and tyrosine kinase inhibitors that target IGF-1R, a transmembrane receptor tyrosine kinase. Enthusiasm for targeting this pathway increased when a randomized phase II study showed that combining an anti-IGF-1R monoclonal antibody (figitumumab) with a platinum doublet resulted in a higher response rate and trends for superior progression-free survival and overall survival. Subsequently, a phase III study failed to confirm the promising results observed in the phase II trial. Currently, investigators are studying different monoclonal antibodies and tyrosine kinases targeting IGF-1R. In unselected patients, results presented thus far do not suggest efficacy of this agent. However, retrospective subgroup analyses suggest that circulating IGF-1 levels might identify patients who could benefit from treatment with an IGF-1R monoclonal antibody and may warrant further exploratory studies for predictive molecular markers. The purpose of this paper is to briefly discuss the IGF pathway and its relationship with other signaling pathways in lung cancer and to review the ongoing IGF clinical trials and efforts to identify predictive molecular markers.

Keywords

epidermal growth factor receptor figitumumab insulin-like growth factor insulin-like growth factor receptor non-small cell lung cancer tyrosine kinase inhibitor

Introduction

Despite advances in medical treatment, lung cancer remains the leading cause of cancer mortality in the United States with 222,520 new cases and 157,300 deaths predicatively described for 2010 [Jemal et al. 2010]. Parallel therapeutic efforts in pathway and biomarker discovery have redefined traditional treatment protocols and added novel targeted therapies to the oncologist’s armamentarium for advanced stage non-small cell lung cancer (NSCLC). Based on preclinical observations and molecular marker studies in patient specimens, the insulin-like growth factor (IGF) pathway has been identified as a promising therapeutic target in lung cancer. Monoclonal antibodies and small molecule inhibitors targeting the IGF-1 receptor (IGF-1R) being tested in both NSCLC and small cell lung cancer (SCLC) are reviewed.

The insulin-like growth factor pathway

The insulin-like growth factor (IGF) pathway is intricate, involving interactions between receptors, ligands, binding proteins, and downstream enzymes. A simian virus 40 transformation model first implicated its role in tumorigenesis in 1993 and since then the IGF pathway components have increasingly been linked to the deregulation of cell growth and metastasis [Douglas et al. 2010; Renehan et al. 2004; Schairer et al. 2004; Sell et al. 1993; Rosendahl et al. 2010; Sarkissvan et al. 2011]. The pathway’s major components consist of IGF-1 and IGF-2 with respective receptors IGF- 1R and IGF-2R as well as IGF binding proteins (IGFBPs) 1–6, and has extensive external regulatory measures (see previous reviews [Firth and Baxter, 2002; Grimberg and Cohen, 2000; Rajaram et al. 1997; Rosenzweig and Atreya, 2010]).

IGF-1 and IGF-2 are structurally related to insulin and function to regulate cell growth, proliferation, transformation, differentiation, migration, and are powerful anti-apoptotic factors [Yu et al. 2000; Lee et al. 2002]. IGF-1 is the systemic mediator of growth hormone (GH) in adults and is secreted by hepatocytes. In neonatal life, IGF-2 is a more important factor for cell differentiation, growth, and maturation, but by adulthood, IGF-1 plays a more significant role despite lower serum concentrations than IGF-2. The two factors are also synthesized at a local tissue level by GH-independent mechanisms and act in a paracrine and autocrine fashion to control cellular growth [Juul et al. 1995; Durai et al. 2005]. Ninety per cent of IGF-1 and IGF-2 is found complexed with IGFBP-3, the most prevalent serum IGF binding protein, and a function-deficient acid labile subunit (ALS) to form a 150 kDa ternary complex [Baxter et al. 1989]. Several research groups have linked increased serum IGF expression as a risk factor for ovarian, pancreatic, prostate, colorectal, lung, and premenopausal breast cancers [Douglas et al. 2010; Lann and LeRoith, 2008; Renehan et al. 2004; Schairer et al. 2004]. In addition, decreased levels of IGFBP-3 have also been associated with the development of malignancy and the malignant phenotype [Douglas et al. 2010; Lee et al. 2002; Zhang et al. 2010].

IGF-1R is a glycoprotein composed of two extracellular alpha subunits that bind IGF-1 preferentially and with lesser affinity to IGF-2 and insulin. The two intracellular beta subunits contain the tyrosine kinase domain responsible for activating the IRS/PI3K/AKT/mTOR pathway and the Ras/Raf/MAPK pathways that promote cell growth, transformation, migration, and survival [Desbois-Mouthon et al. 2009; Ariga et al. 2000; Parrizas et al. 1997; Peruzzi et al. 1999]. Owing to homology to the insulin receptor (IR), most small molecule inhibitors of IGF-1R also target IR, whereas monoclonal antibodies are able to be more IGF-1R specific. Conversely, IGF-2R is a mannose-6-phosphate receptor, has no functional intracellular domain, and ultimately serves to clear IGF-2 from the system.

IGF-1R expression by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) has been detected in 39–84% in patients with advanced NSCLC [Cappuzzo et al. 2006, 2009; Dziadziuszko et al. 2009; Ludovini et al. 2009; Wynes et al. 2009]. This increased expression appears to occur more frequently in squamous cell NSCLC [Cappuzzo et al. 2009; Gualberto et al. 2010]. In early stage NSCLC, the expression of IGF-1R may be less prevalent, found using IHC in only 12.7% of the 125 surgical series examined by Lee and colleagues [Lee et al. 2008]. The prognostic significance of IGF-1R expression by IHC remains unclear. In two independent studies of early stage, resected NSCLC, no statistical association of IGF-1R expression by IHC with survival was found [Cappuzzo et al. 2009; Lee et al. 2008].

IGFBPs 1–6, as well as serum and tissue proteases, are thought to play a role in the IGF pathway and may be markers of tumor activity. IGFBPs are mainly found in free or binary form where they exit capillaries and act at a local tissue level. Most major IGFBPs have both IGF-dependent and independent actions, the former exerted by binding and sequestering IGF and the latter by binding directly to cell membrane and nuclear receptors. IGFBP-3, in particular, displays antiproliferative effects and pro-apoptotic effects both through and independently of the p53 downstream pathway [Buckbinder et al. 1995; Butt et al. 2000; Devi et al. 2000; Santer et al. 2006; Kim et al. 2004]. Levels of serum IGFBPs appear to be prognostic in NSCLC patients whether they are treated with an epidermal growth factor receptor (EGFR) tyrosine kinase receptor (TKI) drug or systemic chemotherapy [Fidler et al. 2009; Karmali et al. 2010]. Similar prognostic significance of IGFBPs was also recently recorded for early stage, surgically resected NSCLC [Shersher et al. 2011]. The intricacies of the IGF-independent action of IGFBPs are beyond the scope of this review but have been described in several cancer models [Chang et al. 2002; Dunlap et al. 2007; Firth and Baxter, 2002; Hoeflich et al. 2001; Li et al. 2010; Migita et al. 2010; Sureshbabu et al. 2009; Walker et al. 2007; Wolpin et al. 2007].

Rationale for combining IGF-1R and EGFR inhibitors

Prognostic evaluation of IGF-1R and EGFR by IHC reveals mixed results depending on the investigator and antibodies used for analysis. IHC analyses in two small retrospective studies suggest that patients with high IGF-1R expression may have improved outcomes on gefitinib therapy compared with those with lower IGF-1R expression [Cappuzzo et al. 2006; Fidler et al. 2008]. In a study by Ludovini and colleagues in surgically treated patients, high co-expression of both IGF-1R and EGFR significantly correlated with worse disease-free survival [Ludovini et al. 2009]. The inconsistency of results for reported IGF-1R expression and outcomes may be related to antibody heterogeneity, bias of scoring systems by IHC, statistically underpowered studies, or the presence of other poorly understood pathways and regulators in an already complex signaling lattice between IGF, EGF, and insulin. Nevertheless, cross-talk between the EGFR, IGF-1R, and IR pathways is supported by preclinical data. Cell-line data suggest that the IGF-1R receptor and downstream pathways are a mechanism of resistance to EGFR TKIs and monoclonal antibodies targeting EGFR, and that targeting both pathways leads to synergistic decreases in downstream signaling [Barnes et al. 2007; Chakravarti et al. 2002; Desbois-Mouthon et al. 2009; Huang et al. 2009; Knowlden et al. 2008; Morgillo et al. 2007; Slomiany et al. 2007]. See Figure 1 for an illustration of interactions between IGF-1R, IR, and EGFR signaling pathways.

Figure 1.

Interactions between insulin-like growth factor-1 receptor (IGF-1R), insulin receptor (IR), and epidermal growth factor receptor (EGFR) signaling pathways. IGF-2R, insulin-like growth factor-2 receptor. The various abbreviations in the diagram refer to known kinases involved in each of the pathways.

The hypothesis that upregulation of IGF-1R signaling in some NSCLC patients contributes mechanistically to EGFR TKI resistance is being tested in clinical trials. In one of these studies, 171 patients were randomized to erlotinib plus one of two doses of R1507 (monoclonal antibody against IGF-1R) versus erlotinib plus placebo. The addition of R1507 failed to show an improvement in 12-week progression-free survival (PFS) in unselected patients. However, circulating levels of IGF-1 were analyzed in 165 patients, and patients whose IGF-1 levels were higher than median had a 46% PFS rate at 12 weeks compared with an 18% PFS rate in patients with IGF-1 levels below the median [Habben et al. 2011]. KRAS mutation analysis was performed in 132 tumor specimens. The KRAS mutation rate was 27% and the 12-week PFS rate for patients with KRAS mutation was 37% with R1507 versus 0% for placebo-treated patients with a hazard ratio (HR) of 0.35, p = 0.012 [Ramalingan et al. 2011]. Despite the interesting results in patient subsets defined by these molecular parameters, it appears that there are no plans for further development of R1507 in NSCLC.

There are several other ongoing trials testing the strategy of inhibiting both the EGFR and IGF-1R pathways. In one study, cetuximab is combined with cixutumumab (an anti-IGF-1R monoclonal antibody). Patients are randomized to gemcitabine–cisplatin or carboplatin–cetuximab with or without cixutumumab. An IGF-1R tyrosine kinase (OSI-906) is being combined with erlotinib in two randomized trials. In the first study, chemotherapy naïve patients with EGFR mutations are randomized to erlotinib combined with OSI-906 or to erlotinib and placebo. In the second study, patients who are eligible for erlotinib maintenance are assigned to the EGFR TKI plus OSI-906 versus placebo.

IGF-1R inhibition and cytotoxic chemotherapy

Preclinical observations which showed that IGF-1R inhibition potentiated the cytotoxic effect of chemotherapeutic agents provided the basis for combinatorial clinical trials [Buck et al. 2008; Casa et al. 2008; Duan et al. 2009]. A randomized, first-line NSCLC phase II study comparing paclitaxel–carboplatin with or without figitumumab (an IgG₂ human monoclonal antibody against IGF-1R) showed higher response rate and longer PFS in figitumumab-treated patients with the best results being observed in squamous cell patients [Karp et al. 2009]. Serum samples were available for 110 of 156 patients in the randomized phase II trial, and, like the phase II trial of R1507 with erlotinib, superior PFS was observed in figitumumab-treated patients who had higher levels of circulating free IGF-1. In addition, circulating levels of IGF-1 were inversely related to tumor tissue expression of E-cadherin and directly related to vimentin expression. Although further validation of these findings is needed, these preliminary observations suggest that circulating free IGF-1 might be a predictive biomarker for figitumumab sensitivity and surrogate for an epithelial-to-mesenchymal transition (EMT) in the tumor, which is implicated in NSCLC therapeutic resistance [Buck et al. 2008; Gualberto et al. 2011].

The phase III trial of carboplatin–paclitaxel with or without figitumumab was disappointing as it was discontinued for futility and there were safety concerns with early fatal toxicities in patients randomized to receive figitumumab. Particularly, early toxicity was noted in patients with low circulating levels of serum IGF. Again, however, in the subset of patients with high IGF serum levels, the addition of figitumumab appeared to offer benefit over carboplatin–paclitaxel [Jassem et al. 2010]. The issue is further complicated as the endocrinology literature notes that low levels of IGF-1 have been correlated with increased mortality [Brugts et al. 2008]. Table 1 lists IGF-1R targeting agents with recently completed and ongoing trials in NSCLC and includes dose-limiting toxicities for these agents. Table 2 summarizes published trials with IGF-1R targeted agents in NSCLC.

Table 1.

Agents in development that target insulin-like growth factor-1 receptor (IGF-1R) in non-small cell lung cancer (NSCLC).

Company	Type	Compound	Combinations	Dose limiting toxicities
Pfizer	IgG₂ Human	Figitumumab (CP-751,871)	Chemotherapy, erlotinib, panHer	None [Haluska et al. 2007]
Imclone	IgG₁ Human	Cixutumumab (IMC-A12)	Single agent, chemotherapy, EGFR (TKI and monoclonal antibody)	Hyperglycemia [Higano et al.2007]
Merck	IgG₁ Humanized	Dalotuzumab (MK-0646)	Single agent, with chemotherapy, with erlotinib	Thrombocytopenia [Hidalgo et al. 2008]
Amgen	IgG₁ Human	AMG 479	Chemotherapy (terminated)	None [Doi et al. 2011]
Biogen Idec	Non-glycosylated IgG₄ Human	BIIB022	With chemotherapy	Cardiac, gastrointestinal bleed [von Mehren et al. 2011]
OSI	Small molecule (also IR)	OSI-906	With erlotinib	Hyperglycemia, transaminitis, fatigue, QTc prolongation, vomiting [Carden et al. 2010; Evans et al. 2010]
Genmab/Roche	IgG₁ Human	R1507	Development halted	None [Rodon et al. 2007; Kurzrock et al. 2010]

EGFR, epidermal growth factor receptor; Ig, immunoglobulin; IR, insulin receptor; TKI, tyrosine kinase inhibitor.

Table 2.

Reported clinical trials of insulin-like growth factor-1 receptor (IGF-1R) targeted agents in non-small cell lung cancer (NSCLC).

Clinical study	Agent classes tested	Number of patients	Type of trial	Findings
Habben et al. [2011] and Ramalingan et al. [2011]	EGFR inhibitor + IGF-1R inhibitor	171	Randomized, placebo controlled phase II trial looking at erlotinib versus erlotinib + R1507	1) High free IGF-1 levels correlate with higher PFS at 12 weeks on 16 mg/kg dose of R1507 2) 12 week PFS benefit in erlotinib + R1507 group in KRAS mutant patients 3) No change in efficacy of erlotinib when adding R1507 in an unspecified population group
Karp et al. [2009] and Gualberto et al. [2010]	IGF-1R inhibitor + cytotoxic chemotherapy	156	Randomized, controlled phase II trial looking at PCF versus PC, with additional nonrandomized 30 patient follow up	1) PCF was well tolerated 2) Better response rate in PCF versus PC group 3) Better response to PCF in squamous cell histology 4) Circulating serum IGF-1 correlated with tissue vimentin and ecadherin expression
Jassem et al. [2010]	IGF-1R inhibitor + cytotoxic chemotherapy	681	Randomized, controlled phase III trial looking at PCF versus PC	1) High grade 4 and 5 toxicity in figitumumab arm 2) Superior OS in patients with low free circulating IGF-1 levels in PC arm 3) Trend toward superior OS in patients with high free circulating IGF-1 levels in PCF arm

EGFR, epidermal growth factor receptor; OS, overall survival; PC, paclitaxel-carboplatin; PCF, paclitaxel-carboplatin-figitumumab; PFS, progression-free survival.

The strategy of combining an IGF-1R inhibitor with cytotoxic agents is also being tested in extensive stage SCLC. The Eastern Cooperative Oncology Group is comparing etoposide– cisplatin–IMC-A12 with the chemotherapy doublet alone. This randomized phase II trial is nearing completion. In the relapsed SCLC setting, OSI-906 is being compared with a single agent, topotecan, in an ongoing study.

IGF-1R and mTOR inhibition

Single-agent trials of mammalian target of rapamycin (mTOR) inhibitors in NSCLC showed these agents were well tolerated but study designed endpoints of response rates were not met [Soria et al. 2009; Molina et al. 2007]. Preclinical data show mTOR inhibition can activate AKT through IGF-1R resulting in a synergistic interaction with IGF-1R inhibitors [Wan et al. 2007; Shi et al. 2005; Kurmasheva et al. 2009; O’Reilly et al. 2006]. This observation led investigators to initiate a phase I trial studying cixutumumab in combination with temsirolimus. The results of the combination showed stable disease in 47% of patients treated [Naing et al. 2011]. With time on therapy, levels of IGF-1 and IGFBP-3 were found to increase although this did not seem to correlate with response rates. Only 1 of 42 patients enrolled in the study had NSCLC and patients with adrenal corticoid carcinoma and Ewing’s sarcoma had the best outcomes. A small trial primarily in sarcoma patients showed a remarkable rate of disease stability (15/18 patients plus one partial response) and no apparent increase in toxicity when an mTOR inhibitor was combined with figitumumab [Quek et al. 2011].

Future directions

The IGF pathway has been implicated in NSCLC pathogenesis for many years, and advancement in research has identified the IGF-1R as a putative target. The negative results in currently reported trials in unselected patients are disappointing, but they do not exclude the possibility that inhibition of the IGF-1R pathway could provide benefit in patients with specific molecular signatures. The preliminary results of presented trials suggest that high circulating levels of IGF-1 may be a potential, easy to test biomarker that may identify patients who may benefit from this class of agents. Currently, the monoclonal antibody IMC-A12 is being tested in combination with a platinum doublet in stage IV NSCLC and in extensive stage SCLC. Although submission of tissue and blood specimens is encouraged in both of these trials, it is unclear whether a sufficient number of specimens will be collected to derive meaningful molecular marker results from these relatively small studies and it is doubtful that significant clinical benefit will be observed with an IGF-1R monoclonal antibody in unselected patients. Ongoing randomized phase II trials will provide the first results for an IGF-1R (OSI-906) TKI combination in NSCLC. In each trial, OSI-906 is combined with erlotinib and submission of blood and tumor specimens for molecular marker testing is mandatory. Considering the large number of novel therapies available for testing and the disappointing results with figitumumab, it seems likely that a strong signal will be required from the ongoing small studies to warrant the continued study of inhibitors of the IGF pathway in lung cancer.

Footnotes

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

MJF has served as an advisor for Bristol Myers Squibb and Genentech and received speaking honoraria from Lilly and Genentech. PB has served as an advisor for Genentech, Lilly, Bristol Myers Squibb.

References

Ariga

Medachi

Akahori

Sakamoto

Ito

Hakuno

(2000) Signalling pathways of insulin-like growth factor-1 that are augmented by cAMP in FRTL-5 cells. Biochem J 348: 409–416.

Barnes

C.J.

Ohshiro

Rayala

S.K.

El-Naggar

A.K.

Kumar

(2007) Insulin-like growth factor receptor as a therapeutic target in head and neck cancer. Clin Cancer Res 13: 4291–4299, DOI: 10.1158/1078-0432.CCR-06-204010.1158/1078-0432.CCR-06-2040.

Baxter

R.C.

Martin

J.L.

Beniac

V.A.

(1989) High molecular weight insulin-like growth factor binding complex. Purification and properties of the acid-labile subunit from human serum. J Biol Chem 264: 11843–11838.

Brugts

M.P.

van den Beld

A.W.

Hofland

L.J.

van der Wansem

van Koetsveld

P.M.

Frystyk

. (2008) Low circulating insulin-like growth factor I bioactivity in elderly men is associated with increased mortality. J Clin Endocrinol Metab 93: 2515–2522, DOI: 10.1210/jc.2007-163310.1210/jc.2007-1633.

Buck

Eyzaguirre

Rosenfeld-Franklin

Thomson

Mulvihill

Barr

. (2008) Feedback mechanisms promote cooperativity for small molecule inhibitors of epidermal and insulin-like growth factor receptors. Cancer Res 68: 8322–8332, DOI: 10.1158/0008-5472.CAN-07-672010.1158/0008-5472.CAN-07-6720.

Buckbinder

Talbott

Velasco-Miguel

Takenaka

Faha

Seizinger

B.R.

. (1995) Induction of the growth inhibitor IGF- binding protein 3 by p53. Nature 377: 646–649, DOI: 10.1038/377646a010.1038/377646a0.

Butt

A.J.

Firth

S.M.

King

M.A.

Baxter

R.C.

(2000) Insulin-like growth factor-binding protein-3 modulates expression of Bax and Bcl-2 and potentiates p53-independent radiation-induced apoptosis in human breast cancer cells. J Biol Chem 275: 39174–39181, DOI: 10.1074/jbc.M90888819910.1074/jbc.M908888199.

Cappuzzo

Tallini

Finocchiaro

Wilson

R.S.

Ligorio

Giordano

. (2009) Insulin-like growth factor receptor 1 (IGF1R) expression and survival in surgically resected non-small-cell lung cancer (NSCLC) patients. Ann Oncol, DOI: 10.1093/annonc/mdp35710.1093/annonc/mdp357.

Cappuzzo

Toschi

Tallini

Ceresoli

G.L.

Domenichini

Bartolini

. (2006) Insulin-like growth factor receptor 1 (IGFR-1) is significantly associated with longer survival in non-small-cell lung cancer patients treated with gefitinib. Ann Oncol 17: 1120–1127, DOI: 10.1093/annonc/mdl07710.1093/annonc/mdl077.

10.

Carden

C.P.

Kim

E.S.

Jones

R.L.

Alam

S.M.

Johnson

F.M.

Stephens

A.W.

. (2010) Phase I study of intermittent dosing of OSI-906, a dual tyrosine kinase inhibitor of insulin-like growth factor-1 receptor and insulin receptor in patients with advanced solid tumors. J Clin Oncol 28(Suppl.): abstract 2530.

11.

Casa

A.J.

Dearth

R.K.

Litzenburger

B.C.

Lee

A.V.

Cui

(2008) The type I insulin-like growth factor receptor pathway: a key player in cancer therapeutic resistance. Front Biosci 13: 3273–3287.

12.

Chakravarti

Loeffler

J.S.

Dyson

N.J.

(2002) Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res 62: 200–207.

13.

Chang

White

M.F.

Fletcher

J.A.

Xiao

(2002) Constitutive activation of insulin receptor substrate 1 is a frequent event in human tumors: therapeutic implications. Cancer Res 62: 6035–6038.

14.

Mouthon

Baron

Blivet-Van Eggelpoel

M.J.

Fartoux

Venot

Bladt

. (2009) Insulin-like growth factor-1 receptor inhibition induces a resistance mechanism via the epidermal growth factor receptor/HER3/AKT signaling pathway: rational basis for cotargeting insulin-like growth factor-1 receptor and epidermal growth factor receptor in hepatocellular carcinoma. Clin Cancer Res 15: 5445–5456, DOI: 10.1158/1078-0432.CCR-08-298010.1158/1078-0432.CCR-08-2980.

15.

Devi

C.R.

Yang

D.H.

Rosenfeld

(2000). Differential effects of insulin-like growth factor binding protein-3 and its proteolytic fragments on ligand binding, cell surface adhesion, Igf-1 receptor signaling. Endocrinology 141: 4171–4179.

16.

Doi

Fuse

Yoshino

Murakami

Yamamoto

Boku

. (2011) Phase I study of AMG 479, a fully human monoclonal antibody against the type 1 insulin-like growth factor receptor in Japanese patients with advanced solid tumors. J Clin Oncol 29(Suppl. 4): abstract 318.

17.

Douglas

J.B.

Silverman

D.T.

Pollak

M.N.

Tao

Soliman

A.S.

Stolzenberg-Solomon

R.Z.

(2010) Serum IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 molar ratio and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev 19: 2298–2306, DOI: 10.1158/1055-9965.EPI-10-040010.1158/1055-9965.EPI-10-0400.

18.

Duan

Choy

Harmon

Yang

Ryu

Schwab

. (2009) Insulin-like growth factor-I receptor tyrosine kinase inhibitor cyclolignan picropodophyllin inhibits proliferation and induces apoptosis in multidrug resistant osteosarcoma cell lines. Mol Cancer Ther 8: 2122–2130, DOI: 10.1158/1535-7163.MCT-09-011510.1158/1535-7163.MCT-09-0115.

19.

Dunlap

S.M.

Celestino

Wang

Jiang

Holland

E.C.

Fuller

G.N.

. (2007) Insulin-like growth factor binding protein 2 promotes glioma development and progression. Proc Natl Acad Sci U S A 104: 11736–11741, DOI: 10.1073/pnas.070314510410.1073/pnas.0703145104.

20.

Durai

Yang

Gupta

Seifalian

A.M.

Winslet

M.C.

(2005) The role of the insulin-like growth factor system in colorectal cancer: review of current knowledge. Int J Colorectal Dis 20: 203–220, DOI: 10.1007/s00384-004-0675-410.1007/s00384-004-0675-4.

21.

Dziadziuszko

Camidge

D.R.

Hirsch

F.R.

(2008) The insulin-like growth factor pathway in lung cancer. J Thorac Oncol 3: 815–818, DOI: 10.1097/JTO.0b013e31818180f510.1097/JTO.0b013e31818180f5.

22.

Dziadziuszko

Merrick

D.T.

Witta

A.D.

Mendoza

Szostakiewicz

(2009) Insulin-like growth factor receptor 1 protein expression, mRNA expression and gene copy number in operable non-small cell lung cancer. J Clin Oncol 27: 7524.

23.

Evans

Lindsay

C.R.

Chan

Tait

Michael

S.A.

Day

. (2010) Phase I dose-escalation study of continuous oral dosing of OSI-906, a dual tyrosine kinase inhibitor of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR) in patients with advanced solid tumors. J Clin Oncol 28(Suppl.): abstract 2531.

24.

Fidler

M.J.

Basu

Buckingham

Kaiser

McCormack

Coon

. (2008) Insulin-like growth factor receptor-1 and outcome measures in advanced NSCLC patients treated with gefitinib. J Clin Oncol 26 (Suppl. 20 May): abstract 8036.

25.

Fidler

M.J.

Gimelfarb

Dehghan-Paz

Basu

Fhied

Kaiser

. (2009) Insulin-like binding proteins and response in advanced NSCLC patients treated with erlotinib. J Thorac Oncol: PD 7.3.5.

26.

Firth

S.M.

Baxter

R.C.

(2002) Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev 23: 824–854.

27.

Grimberg

Cohen

(2000) Role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis. J Cell Physiol 183: 1–9.

28.

Gualberto

Dolled-Filhart

Gustavson

Christiansen

Wang

Y.F.

Hixon

M.L.

. (2010) Molecular analysis of non-small cell lung cancer identifies subsets with different sensitivity to insulin-like growth factor I receptor inhibition. Clin Cancer Res 16: 4654–4665, DOI: 10.1158/1078-0432.CCR-10-0089.

29.

Gualberto

Hixon

M.L.

Karp

D.D.

Green

Dolled-Filhart

. (2011) Pre-treatment levels of circulating free IGF-1 identify NSCLC patients who derive clinical benefit from figitumumab. Br J Cancer 104: 68–74, DOI: 10.1038/sj.bjc.660597210.1038/sj.bjc.6605972.

30.

Habben

Delmar

Brownstein

C.M.

Koehler

Kuenkele

Spiesis

. (2011) Investigation of predictive biomarkers for R1507, an anti-IGF1R antibody in patients with advanced non-small cell lung cancer with progression after first-line chemotherapy. J Clin Oncol 29(Suppl.): abstract 7584.

31.

Haluska

Shah

Batzel

Molife

L.R.

Adjei

A.A.

Yap

T.A.

. (2007) Phase I dose escalation study of the anti-IGF-1R monoclonal antibody in refractory solid tumors. J Clin Oncol 25(Suppl.): abstract 3586.

32.

Higano

C.S.

E.Y.

Whiting

S.H.

Gordon

M.S.

Lorusso

Fox

. (2007) Phase I, first in man study of weekly IMC-A12, a fully human insulin like growth factor-I receptor IgG1 monoclonal antibody, in patients with advanced solid tumors. 2007 Prostate Cancer Symposium, abstract 269.

33.

Hildago

Tirado Gomez

Lewis

Vuky

J.L.

Taylor

Hayburn

J.L.

. (2008) A phase I study of MK-0646, a humanized monoclonal antibody against the insulin like growth factor receptor type 1 in advanced solid tumor patients in a q2week schedule. J Clin Oncol 26(Suppl.): abstract 3520.

34.

Hoeflich

Reisinger

Lahm

Kiess

Blum

W.F.

Kolb

H.J.

. (2001) Insulin-like growth factor-binding protein 2 in tumorigenesis: protector or promoter? Cancer Res 61: 8601–8610.

35.

Huang

Greer

Hurlburt

Han

Hafezi

Wittenberg

G.M.

. (2009) The mechanisms of differential sensitivity to an insulin-like growth factor-1 receptor inhibitor (BMS-536924) and rationale for combining with EGFR/HER2 inhibitors. Cancer Res 69: 161–170, DOI: 10.1158/0008-5472.CAN-08-0835.

36.

Jassem

Langer

C.M.

Karp

D.D.

Mok

Benner

R.J.

Green

S.J.

. (2010) Randomized, open label, phase III trial of figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin in patients with non-small cell lung cancer. J Clin Oncol 28(15 Suppl.): abstract 7500.

37.

Jemal

Center

M.M.

DeSantis

Ward

E.M.

(2010) Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev 19: 1893–1907, DOI: 10.1158/ 1055-9965.EPI-10-043710.1158/ 1055-9965.EPI-10-0437.

38.

Juul

Scheike

Nielsen

C.T.

Krabbe

Müller

Skakkebaek

N.E.

(1995) Serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 levels are increased in central precocious puberty: effects of two different treatment regimens with gonadotropin-releasing hormone agonists, without or in combination with an antiandrogen (cyproterone acetate). J Clin Endocrinol Metab 80(10):3059–67.

39.

Karmali

Fidler

M.J.

Cela

Olmsted

Rouhi

Basu

. (2010) Insulin like growth factor binding proteins related to progression free survival and overall survival in advanced non-small cell lung cancer patients treated with chemotherapy. J Clin Oncol 28: 15s, abstract 7553.

40.

Karp

D.D.

Paz-Ares

L.G.

Novello

Haluska

Garland

Cardenal

. (2009) Phase II study of the anti-insulin-like growth factor type 1 receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer. J Clin Oncol 27: 2516–2522, DOI: 10.1200/JCO.2008.19.933110.1200/JCO.2008.19.9331.

41.

Kim

H.S.

Ingermann

A.R.

Tsubaki

Twigg

S.M.

Walker

G.E.

(2004) Insulin-like growth factor-binding protein 3 induces caspase-dependent apoptosis through a death receptor-mediated pathway in MCF-7 human breast cancer cells. Cancer Res 64: 2229–2237.

42.

Knowlden

J.M.

Jones

H.E.

Barrow

Gee

J.M.

Nicholson

R.I.

Hutcheson

I.R.

(2008) Insulin receptor substrate-1 involvement in epidermal growth factor receptor and insulin-like growth factor receptor signalling: implication for Gefitinib (‘Iressa’) response and resistance. Breast Cancer Res Treat 111: 79–91, DOI: 10.1007/s10549-007-9763-910.1007/s10549-007-9763-9.

43.

Kurmasheva

R.T.

Dudkin

Billups

Debelenko

L.V.

Morton

C.L.

Houghton

P.J.

(2009) The insulin-like growth factor-1 targeting antibody, CP-751871, suppresses tumor-derived VEGF and synergizes with rapamycin in models of childhood sarcoma. Cancer Res 69: 7662–7671.

44.

Kurzrock

Patnaik

Aisner

Warren

Leong

Benjamin

. (2010) A phase I study of weekly R1507, a human monoclonal antibody IGF-1R antagonist, in patients with advanced cancer. Clin Cancer Res 16: 2458–2465.

45.

Lann

LeRoith

(2008) The role of endocrine insulin-like growth factor-I and insulin in breast cancer. J Mammary Gland Biol Neoplasia 13: 371–379, DOI: 10.1007/s10911-008-9100-x10.1007/s10911-008-9100-x.

46.

Lee

C.Y.

Jeon

J.H.

Kim

H.J.

Shin

D.H.

Roh

T.W.

Ahn

C.M.

. (2008) Clinical significance of insulin-like growth factor-1 receptor expression in stage I non-small-cell lung cancer: immunohistochemical analysis. Korean J Intern Med 23: 116–120, DOI: 10.3904/kjim.2008.23.3.11610.3904/kjim.2008.23.3.116.

47.

Lee

H.Y.

Chun

K.H.

Liu

Wiehle

S.A.

Cristiano

R.J.

Hong

W.K.

. (2002) Insulin-like growth factor binding protein-3 inhibits the growth of non-small cell lung cancer. Cancer Res 62: 3530–3537.

48.

Huang

Huo

(2010) IGFBP3 polymorphisms and risk of cancer: a meta-analysis. Mol Biol Rep 37: 127–140, DOI: 10.1007/s11033-009-9552-010.1007/s11033-009-9552-0.

49.

Ludovini

Bellezza

Pistola

Bianconi

Di Carlo

Sidoni

. (2009) High coexpression of both insulin-like growth factor receptor-1 (IGFR-1) and epidermal growth factor receptor (EGFR) is associated with shorter disease-free survival in resected non-small-cell lung cancer patients. Ann Oncol 20: 842–849, DOI: 10.1093/annonc/mdn72710.1093/annonc/mdn727.

50.

Migita

Narita

Asaka

Miyagi

Nagano

Nomura

. (2010) Role of insulin-like growth factor binding protein 2 in lung adenocarcinoma: IGF-independent antiapoptotic effect via caspase-3. Am J Pathol 176: 1756–1766, DOI: 10.2353/ajpath.2010.090500.

51.

Molina

Mandrekar

Rowland

Reuter

Jett

J.R.

Marks

. (2007) A phase II NCCTG “Window of Opportunity Front-line” study of the mTOR Inhibitor, CCI-779 (Temsirolimus) given as a single agent in patients with advanced NSCLC: D7-07. J Thorac Oncol 2(Suppl.): abstract S413.

52.

Morgillo

Kim

W.Y.

Kim

E.S.

Ciardiello

Hong

W.K.

Lee

H.Y.

(2007) Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res 13: 2795–2803, DOI: 10.1158/1078-0432.CCR-06-207710.1158/1078-0432.CCR-06-2077.

53.

Naing

Kurzrok

Burger

Gupta

Lei

Busaidy

. (2011) Phase I trial of cixutumumab combined with temsirolimus in patients with advanced cancer. Clin Cancer Res, DOI: 10.1158/1078-0432.CCR-10-297910.1158/1078-0432.CCR-10-2979.

54.

O’Reilly

K.E.

Rojo

She

Q.B.

Solit

Mills

G.B.

Smith

. (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66: 1500–1508.

55.

Parrizas

Saltiel

A.R.

Le Roith

(1997) Insulin-like growth factor-1 inhibits apoptosis using the phosphatidylinositol 3’kinase and mitogen-activated protein kinase pathways. J Biol Chem 272: 154–161.

56.

Peruzzi

Prisco

Dews

Salomoni

Grassilli

Romano

. (1999) Multiple signaling pathways of the insulin-like growth factor 1 receptor in the protection from apoptosis. Mol Cellular Biol 19: 7203–7215.

57.

Quek

Wang

Morgan

J.A.

Shapiro

G.I.

Butrynski

J.E.

Ramaiya

. (2011) Combination mTOR and IGF-1R inhibition: phase I trial of everolimus and figitumumab in patients with advanced sarcomas and other solid tumors. Clin Cancer Res 17: 871–879, DOI: 10.1158/1078-0432.CCR-10-262110.1158/1078-0432.CCR-10-2621.

58.

Rajaram

Baylink

D.J.

Mohan

(1997) Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocr Rev 18(6):801–31.

59.

Ramalingan

S.S.

Spigel

D.R.

Steins

Engelman

J.A.

Schneider

Novello

. (2011) Randomized, double-blind, phase II study of erlotinib in combination with placebo or R1507. a monoclonal antibody to insulin-like growth factor receptor-1 (IGF-1R) for advanced-stage non-small cell lung cancer (NSCLC). J Clin Oncol 29(Suppl.): abstract 7527.

60.

Renehan

A.G.

Zwahlen

Minder

O’Dwyer

S.T.

Shalet

S.M.

Egger

(2004) Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 363: 1346–1353, DOI: 10.1016/S0140-6736(04)16044-3.

61.

Rodon

Patnaik

Stein

Tocher

Dias

. (2007) A phase I study of q3W R1507, a human monoclonal antibody IGF-1R antagonist in patients with advanced cancer. J Clin Oncol 25(Suppl.): abstract 3590.

62.

Rosendahl

A.H.

Hietala

Henningson

Olsson

Jernstrom

(2011) IGFBP1 and IGFBP3 polymorphisms predict circulating IGFBP-3 levels among women from high-risk breast cancer families. Breast Cancer Res Treatment 127: 785–794.

63.

Rosenzweig

S.A.

Atreya

H.S.

(2010) Defining the pathway to insulin-like growth factor system targeting in cancer. Biochem Pharmacol 80: 1115–1124, DOI: 10.1016/j.bcp.2010.06.01310.1016/j.bcp.2010.06.013.

64.

Santer

F.R.

Bacher

Moser

Morandeli

Ressler

Firth

S.M.

. (2006) Nuclear insulin-like growth factor binding protein-3 induces apoptosis and is targeted to ubiquitin/proteasome-dependent proteolysis. Cancer Res 66: 3024–3033.

65.

Sarkissvan

Mishra

D.K.

Shang

Sarkissvan

Vadgama

J.V.

(2011) IGF gene polymorphisms and breast cancer in African-American and Hispanic women. Int J Oncol 38: 1663–1673.

66.

Schairer

Hill

Sturgeon

S.R.

Fears

Pollak

Mies

. (2004) Serum concentrations of IGF-I, IGFBP-3 and c-peptide and risk of hyperplasia and cancer of the breast in postmenopausal women. Int J Cancer 108: 773–779, DOI: 10.1002/ijc.11624.

67.

Sell

Rubini

Rubin

Liu

J.P.

Efstratiadis

Baserga

(1993) Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor. Proc Natl Acad Sci U S A 90: 11217–11221.

68.

Shersher

D.D.

Vercillo

M.S.

Fhied

Basu

Rouhi

Mahon

. (2011) insulin-like growth factor binding proteins related to disease-free survival in non-small cell lung cancer (NSCLC) patients treated with surgery. Ann Thorac Surg (accepted for publication).

69.

Shi

Yan

Frost

Gera

Lichtenstein

(2005) mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by upregulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Mol Cancer Ther 4: 1533–1540.

70.

Slomiany

M.G.

Black

L.A.

Kibbey

M.M.

Tingler

M.A.

Day

T.A.

Rosenzweig

S.A.

(2007) Insulin-like growth factor-1 receptor and ligand targeting in head and neck squamous cell carcinoma. Cancer Lett 248: 269–279, DOI: 10.1016/j.canlet.2006.08.00410.1016/j.canlet.2006.08.004.

71.

Soria

J.C.

Shepherd

F.A.

Douillard

J.Y.

Wolf

Giaccone

Crino

. (2009) Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. Ann Oncol 20: 1674–1681.

72.

Sureshbabu

Okajima

Yamanaka

Shastri

Tonner

Rae

. (2009) IGFBP-5 induces epithelial and fibroblast responses consistent with the fibrotic response. Biochem Soc Trans 37: 882–885, DOI: 10.1042/BST 037088210.1042/BST 0370882.

73.

von Mehren

Britten

Lear

Bamidge

D.R.

Wainberg

Z.A.

Pieslor

P.C.

. (2011) Phase I, dose-escalation study of BIIB022 (anti-IGF-1R antibody) in advanced solid tumors. J Clin Oncol 28(Suppl.): abstract 2612.

74.

Walker

MacLeod

Williams

A.R.

Cameron

D.A.

Smyth

J.F.

Langdon

S.P.

(2007) Insulin-like growth factor binding proteins IGFBP3, IGFBP4, and IGFBP5 predict endocrine responsiveness in patients with ovarian cancer. Clin Cancer Res 13: 1438–1444, DOI: 10.1158/1078-0432.CCR-06-2245.

75.

Wan

Harkavy

Shen

Grohar

Heiman

L.J.

(2007) Rapamycin induces feedback activation of Akt signaling through an IGF-1R dependent mechanism. Oncogene 26: 1392–1340.

76.

Wolpin

B.M.

Michaud

D.S.

Giovannucci

E.L.

Schernhammer

E.S.

Stampfer

M.J.

Manson

J.E.

. (2007) Circulating insulin-like growth factor binding protein-1 and the risk of pancreatic cancer. Cancer Res 67: 7923–7928, DOI: 10.1158/0008-5472.CAN-07-037310.1158/0008-5472.CAN-07-0373.

77.

Wynes

M.W.

Singh

Dziadziuszko

Jaskewicz

Jassem

(2009) Analysis of IGF1R gene copy number by silver in situ hybridization in non-small cell lung cancer. J Clin Oncol 27: 7525.

78.

Rohan

(2000) Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst 92(18):1472–89.

79.

Zhang

Fagan

D.H.

Zeng

Freeman

K.T.

Sachdev

Yee

(2010) Inhibition of cancer cell proliferation and metastasis by insulin receptor downregulation. Oncogene 29: 2517–2527, DOI: 10.1038/onc.2010.1710.1038/onc.2010.17.