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. Author manuscript; available in PMC: 2016 Oct 1.
Published in final edited form as: Clin Cancer Res. 2015 Oct 1;21(19):4270–4277. doi: 10.1158/1078-0432.CCR-14-2518

Molecular Pathways: Clinical Applications and Future Direction of Insulin-Like Growth Factor-1 Receptor Pathway Blockade

Wade T Iams 1, Christine M Lovly 1,2,3,*
PMCID: PMC4593065  NIHMSID: NIHMS714401  PMID: 26429980

Abstract

The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is a complex and tightly regulated network which is critical for cell proliferation, growth, and survival. IGF-1R is a potential therapeutic target for patients with many different malignancies. This brief review summarizes the results of clinical trials targeting the IGF-1R pathway in patients with breast cancer, sarcoma, and non-small cell lung cancer (NSCLC). Therapeutic agents discussed include both monoclonal antibodies to IGF-1R (dalotuzumab, figitumumab, cixutumumab, ganitumab, R1507, AVE1642) and newer IGF-1R pathway targeting strategies including monoclonal antibodies to IGF-1 and IGF-2 (MEDI-573 and BI 836845) and a small molecule tyrosine kinase inhibitor of IGF-1R (OSI-906). The pullback of trials in patients with breast cancer and NSCLC based on several large negative trials is noted and contrasted with the sustained success of IGF-1R inhibitor monotherapy in a subset of patients with sarcoma. Several different biomarkers have been examined in these trials with varying levels of success, including tumor expression of IGF-1R and its pathway components, serum IGF ligand levels, alternate pathway activation, and specific molecular signatures of IGF-1R pathway dependence. However, there remains a critical need to define predictive biomarkers in order to identify patients who may benefit from IGF-1R directed therapies. Ongoing research focuses on uncovering such biomarkers and elucidating mechanisms of resistance, as this therapeutic target is currently being analyzed from the bedside to bench.

Background

The Insulin-Like Growth Factor (IGF) signaling pathway is a complex and tightly regulated network which is critical for cell proliferation and survival (1). This pathway (Fig. 1) is composed of three receptor tyrosine kinases - insulin-like growth factor-1 receptor (IGF-1R), insulin-like growth factor-2 receptor (IGF-2R), and insulin receptor (INSR); three ligands – insulin, IGF-1, and IGF-2 (2, 3); and six serum Insulin-like Growth Factor Binding Proteins (IGFBP’s), which serve as regulators of the pathway by determining ligand bioavailability (4). The most prevalent of the IGFBP’s is IGFBP3 (5). Both IGF-1 and IGF-2 exert their effects through autocrine, paracrine, and endocrine mechanisms, and both can activate IGF-1R signaling.

Figure 1.

Figure 1

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Schematic representation of the IGF-1R signaling network and nodes of therapeutic blockade. The IGF-1R signaling pathway is composed of three receptor tyrosine kinases - insulin-like growth factor-1 receptor (IGF-1R), insulin-like growth factor-2 receptor (IGF-2R), and insulin receptor (INSR); three ligands – Insulin, IGF-1, and IGF-2 (formerly known as somatomedins) (1, 2); and six serum Insulin-like Growth Factor Binding Proteins (IGFBPs). The IGFBPs, of which IGFBP3 is the most common, serve as regulators of the pathway by determining the bioavailability of IGF-1 and IGF-2 ligands (4). Both IGF-1 and IGF-2 exert their effects through autocrine, paracrine, and endocrine mechanisms, and both can activate the IGF-1R pathway. For simplification, IGF-1 ligand only is shown binding to IGF-1R. IGF-1 binding to IGF-1R promotes receptor homodimerization or heterodimerization with INSR. Ligand-activated IGF-1R first binds to intracellular adaptor proteins, such as insulin receptor substrate1 (IRS1) and SHC. These adaptor proteins transmit signals through the phosphatidyl-inositol-3 kinase (PI3K)-AKT1-mammalian target of rapamycin (MTOR) pathway and through the mitogen activated protein kinase (MAPK) pathway. Activated IGF-1R promotes cellular motility through activation of IRS2, which alters integrin expression through poorly understood mechanisms involving the small G protein RHOA, focal adhesion kinase (FAK), Rho-kinase (ROCK), PI3K, and other signaling molecules. Of note, IGF2R is a repository for IGF-2, and it has no intracellular signaling activity. IGF-2R acts as a tumor suppressor gene, as when IGF-2R function is lost, IGF-2 is able to bind IGF-1R and promote tumorigenesis (17). Targets for potential monotherapy and combinatorial therapeutic strategies are noted in the figure. TKI: tyrosine kinase inhibitor. mAb: monoclonal antibody.

IGF-1R is a type 2 tyrosine kinase transmembrane receptor that is normally found as a heterotetramer with two alpha and two beta subunits (6, 7). IGF-1R binding to IGF-1 or IGF-2 can occur with IGF-1R as a homodimer or as a heterodimer with insulin receptor isoforms A or B (INSR-A, INSR-B) (2, 8). While the heterodimer IGF-1R/INSR can bind insulin, it has been shown to preferentially favor IGF-1 mediated signaling (9, 10).

Once activated, IGF-1R activates numerous downstream pathways within the cell. In order to propagate these signals, ligand activated IGF-1R first binds to intracellular adaptor proteins – predominantly insulin receptor substrate1 (IRS1) (11), although other intracellular proteins such as SHC1 (12), GAB (13), and CRK (14) can interact with activated IGF-1R. These adaptor proteins are necessary for IGF-1R to transmit signals downstream in the cell through the phosphatidyl-inositol-3 kinase (PI3K)-AKT1- mammalian target of rapamycin (MTOR) pathway and through the mitogen activated protein kinase (MAPK) pathway. Ligand-activated IGF-1R binds to IRS1, which then binds to the p85 regulatory subunit of PI3K, which then transmits signals to AKT1 and MTOR. Activation of the PI3K-AKT1-MTOR pathway results in pleiotropic effects, including inactivation of the pro-apoptotic protein BAD (15–19). Concurrently, IGF-1R binds to SHC, which interacts with growth factor receptor-bound-2 (GRB2)-son-of-sevenless (SOS) to activate the MAPK pathway (14). Finally, activated IGF-1R is thought to promote cellular motility through activation of IRS2, which acts to alter integrin expression through poorly understood mechanisms involving the small G protein RHOA, focal adhesion kinase (FAK), and Rho-kinase (ROCK) (15, 16). Of note, IGF-2R is a repository for IGF-2, and it has no intracellular signaling activity. In this capacity, IGF-2R acts as a tumor suppressor gene, as when IGF-2R function is lost, IGF-2 is able to bind IGF-1R and promote tumorigenesis (17).

Serum IGF-1 and IGFBP3 levels are normally regulated by the pituitary gland (18, 19). Elevated serum levels of IGF-1 and IGF-2 as well as overactivation of the mitogenic, anti-apoptotic, and pro-motility signaling cascades induced by IGF-1R have been implicated in many tumor types, including epithelial malignancies (breast, lung, colorectal, prostate, ovarian), mesenchymal tumors (osteosarcoma, rhabdomyosarcoma), and hematologic malignancies (1, 2, 17, 20, 21). Furthermore, IGF-1R pathway dysregulation acts as an oncogenic signal in the context of both initial tumorigenesis and resistance to cytotoxic and targeted anticancer therapies (2, 3, 22, 23).

Herein, we focus on the role of the IGF-1R pathway in breast cancer, sarcoma, and non-small cell lung cancer (NSCLC), as it is in these three malignancies that IGF-1R pathway blockade has been most extensively studied. In patients with breast cancer, it has been noted that the IGF-1R pathway has extensive crosstalk with the estrogen receptor (ER) and epidermal growth factor receptor 2 (ERBB2) signaling pathways, and IGF-1R has been implicated in resistance to hormonal therapy (24, 25). Furthermore, IGF-1R is directly upstream of the PI3K-AKT1-MTOR pathway, which is aberrantly activated in more than half of human breast cancers (26). Preclinical data in sarcoma tumor models has shown that the IGF-1R pathway is particularly important in tumor growth, metastasis, and angiogenesis in patients with Ewing’s sarcoma and rhabdomyosarcoma, leading to the initial application of IGF-1R inhibitors in patients with these tumor types (27). Finally, IGF-1R protein levels have been shown to be high in NSCLC cell lines and patient samples, both in adenocarcinoma and squamous histologies (28, 29). Also, IGF-1R expression is associated with poor prognosis in patients with NSCLC (28). It is worth mentioning that IGF-1R expression levels have been evaluated in small cell lung cancer (SCLC), however we will only discuss NSCLC.

Numerous therapeutic agents targeting the IGF-1R pathway have been developed. These agents include IGF-1R monoclonal antibodies (mAbs), IGF-1R/INSR tyrosine kinase inhibitors (TKIs), and more recently, IGF-1 and IGF-2 specific mAbs (Fig. 1). Furthermore, several rational combination therapeutic strategies have been employed to attempt to more potently inhibit IGF-1R signaling. To date, the most widely tested combination strategy involves the use of IGF-1R antibodies with MTOR allosteric inhibitors, such as temsirolimus (30) or ridaforolimus (3). There is established pre-clinical rationale for this approach, as numerous studies have now shown that MTOR inhibition paradoxically results in activation of the IGF-1R pathway (31).

In the following sections we describe the current state and future directions of the application of IGF-1R targeting agents in patients with breast cancer, sarcoma, and NSCLC, with a summary of the high-impact trials provided in Table 1.

Table 1.

Published clinical trials involving IGF-1R pathway inhibition in patients with breast cancer, sarcoma, or lung cancer

Reference Phase n Tumor types Therapy Disease control rates
Atzori et al., 2011 (32) I 80 Colorectal (24%), breast (21%), sarcoma (11%), other (43%) Dalotuzumab (MK-0646) SD 8%, PR 4%, CR 0%
Di Cosimo et al., 2015 (36) I 87 Breast (26%), colorectal (22%), NSCLC (18%), sarcoma (16%), other (18%) Dalotuzumab (MK-0646) + ridaforolimus SD 46%, PR 7%, CR 0%
Higano et al., 2015 (33) I 40 Lung (20%), colon (15%), breast (7.5%), other (57.5%) Cixutumumab (IMC-A12) SD 25%, PR 0%, CR 0%
Ma et al., 2013 (37) I 26 Breast (100%); ER positive (86%) Cixutumumab (IMC-A12) + temsirolimus SD 15%, PR 0%, CR 0%
Naing et al., 2011 (19) I 42 Adrenocortical (24%), breast (21%), sarcoma (21%), other (41%) Cixutumumab (IMC-A12) + temsirolimus SD 43%, PR 0%, CR 0%
Tolcher et al., 2009 (34) I 53 Sarcoma (42%), other (58%) Ganitumab (AMG-479) SD NA, PR 4%, CR 2%
Goto et al., 2012 (47) I 19 NSCLC (100%) Figitumumab (CP-751,871) + carboplatin and paclitaxel SD 42%, PR 37%, CR 0%
Molife et al., 2010 (45) I 46 Prostate (48%), esophageal (20%), sarcoma (6.5%), NSCLC (4.3%), other (21.2%) Figitumumab (CP-751,871) + docetaxel SD 26%, PR 9%, CR 0%
Murakami et al., 2012 (5) I 19 Breast (21%), gastric (16%), NSCLC (10%), sarcoma (10%), other (43%) Ganitumab (AMG-479) SD 37%, PR 0%, CR 0%
Kurzrock et al., 2010 (35) I 35 Sarcoma (51%), lung (5.5%), breast (5.5%), other (38%) R1507 SD 35%, PR 5%, CR 0%
Macaulay et al., 2013 (18) I 58 Ovarian (21%), sarcoma (9%), breast (7%), NSCLC (5%), other (58%) AVE1642 + docetaxel OR gemcitabine/erlotinib OR doxorubicin SD 40–70%, PR 2.5–20%, CR 0%
Puzanov et al., 2014 (8) I 86 Colorectal (49%), NSCLC (4%), sarcoma (4%), other (43%) OSI-906 SD 36%, PR 1%, CR 0%
Haluska et al., 2014 (50) I 43 Urothelial (46.5%), sarcoma (9%), colorectal (5%), breast (2.5%), MEDI-573 SD 30%, PR 0%, CR 0%
Haluska et al., 2007 (39) I 24 NSCLC (2.5%), other (34.5%) Colorectal (25%), lung (17%), sarcoma (17%), other (41%) Figitumumab (CP-751,871) SD 41%, PR 0%, CR 0%
Olmos et al., 2010 (27) I 29 Sarcoma (100%); Ewing’s sarcoma (55%) Figitumumab (CP-751,871) SD 28.5%, PR 3.5%, CR 3.5%
Naing et al., 2012 (30) I 20 Ewing’s sarcoma (85%), desmoplastic small round cell tumor (15%) Cixutumumab (IMC-A12) + temsirolimus SD 25%, PR 0%, CR 10%
Quek et al., 2011 (43) I 21 Sarcoma (90%), adrenal cortical (5%), colorectal (5%) Figitumumab (CP-751,871) + everolimus SD 71%, PR 5%, CR 0%
Juergens et al., 2011 (40) I/II 31 (I)
107 (II)		 Sarcoma (100%); Ewing’s sarcoma (89%) Figitumumab (CP-751,871) SD 24%, PR 14%, CR 0%
Schoffski et al., 2013 (42) II 111 Sarcoma (100%); Ewing’s sarcoma (18%) Cixutumumab (IMC-A12) SD 40%, PR 2%, CR 0%
Schwartz et al., 2013 (44) II 174 Sarcoma (100%); Ewing’s sarcoma (15.5%) Cixutumumab (IMC-A12) + temsirolimus SD 38%, PR 5%, CR 0%
Pappo et al., 2011 (41) II 115 Ewing’s sarcoma (100%) R1507 SD 16%, PR 9%, CR 1%
Karp et al., 2009 (48) II 98 NSCLC (100%) Figitumumab (CP-751,871) + carboplatin and paclitaxel SD 10–20%, PR + CR 54% -> 37% corrected
Robertson et al., 2013 (38) II 63 Breast (100%); ER positive (94%) Ganitumab (AMG-479) + fulvestrant OR exemestane SD 27%, PR 8%, CR 0%
Ramalingam et al., 2011 (49) II 172 NSCLC (100%) Erlotinib +/− R1507 12-week PFS: 41%/43.5%
OS: 8.1 mo/10 mo
Langer et al., 2014 (46) III 338 NSCLC (nonadenocarcinoma 100%) Figitumumab (CP-751,871) + carboplatin and paclitaxel SD not noted
PR + CR 33%
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Abbreviations: CR, complete response; ER, estrogen receptor; mo, months; NA, not available; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression free survival; PR, partial response; SD, stable disease.

Clinical-Translational Advances

IGF-1R pathway inhibition in patients with breast cancer

There have been four different anti-IGF1R mAbs tested in early clinical trials involving small numbers of patients with advanced, treatment refractory breast cancer with largely unimpressive results (5, 32–35). Consequently, three phase I clinical trials assessing the combination of IGF-1R mAbs with MTOR inhibitors in patients with advanced, treatment refractory breast cancer have been completed (19, 36, 37). In a phase I clinical trial with dalotuzumab and the MTOR inhibitor ridaforolimus, a subset of patients with ER positive (ER+), highly proliferative disease was shown to have exceptional responses, experiencing a disease control rate (stable disease [SD] plus partial response [PR]) of 55% (6/11 patients). These promising results created momentum for a recently completed phase II clinical trial involving patients with advanced luminal B breast cancer treated with dalotuzumab, ridaforolimus, and hormonal therapy (NCT01234857) (36). In a phase I clinical trial with cixutumumab and the MTOR inhibitor temsirolimus, among 26 patients with breast cancer (86% with ER+ disease), four (15%) had SD, and no PRs or complete responses (CRs) were observed. The results of this trial, in which the median number of prior chemotherapeutic regimens was three, stimulated interest in testing the combination of cixutumumab and temsirolimus in patients with metastatic breast cancer and no more than two prior lines of chemotherapy, but initial trial results have shown no tumor responses (NCT00699491) (37). Finally, unlike combination with MTOR inhibition, the combination of IGF-1R inhibition with exemestane or fulvestrant in patients with advanced breast cancer was unsuccessful in a phase II trial (38), halting the application of combination hormonal therapy and IGF-1R inhibition in patients with breast cancer.

IGF-1R pathway inhibition in patients with sarcoma

Due to successful initial clinical trials in patients with advanced, treatment refractory sarcoma treated with IGF-1R mAbs (5, 32, 34, 35, 39), larger trials with a combined total of 362 patients have been completed (27, 40–42). In summation of these clinical trials, disease stabilization rates have been 16–40%, PRs have ranged from 2–12% of patients, and two of 362 patients have achieved a CR. Overall, the exceptional response of some patients to IGF-1R inhibitor monotherapy has led to speculation that a subset of patients with sarcoma, especially Ewing’s sarcoma, are uniquely dependent on IGF-1R signaling (19).

The combination of MTOR inhibition with IGF-1R inhibition in patients with advanced sarcoma has yielded similar results to IGF-1R monotherapy (19, 30, 36, 43, 44), and the combination of IGF-1R inhibition with cytotoxic chemotherapy has yielded provocative results in patients with leiomyosarcoma (18, 45). Overall, the clinical trials of anti-IGF-1R mAbs in patients with sarcoma have shown occasionally profound responses and disease stabilization rates ranging from 16% to up to 70% when IGF-1R mAbs have been combined with MTOR inhibitors (43). However, larger trials are needed to determine the optimal therapeutic strategy (monotherapy versus combination therapy with MTOR inhibitors) and also to parse out which subset of patients are most likely to benefit.

IGF-1R pathway inhibition in patients with non-small cell lung cancer

The combination of IGF-1R inhibition with cytotoxic chemotherapy has been tested in several large clinical trials in patients with NSCLC (46–48). The most well-studied IGF-1R mAb in lung cancer is figitumumab. When the combination of figitumumab, carboplatin, and paclitaxel was used as first line therapy in 98 patients with advanced NSCLC, the objective response rate (ORR) was initially reported as 57%, with an additional 10–20% of patients experiencing SD (48). These encouraging results prompted the completion of a phase III trial comparing figitumumab plus carboplatin/paclitaxel to carboplatin/paclitaxel alone in patients with treatment naïve advanced NSCLC. This clinical trial was closed early due to increased rates of serious adverse events and treatment related deaths in patients treated with figitumumab (46). The phase III trial showed an ORR of 33% for the figitumumab plus carboplatin/paclitaxel arm, and rather than the initially reported 54% ORR in the phase II trial, the actual observed rate was 37%) (46). The serious adverse events that were observed more commonly in patients receiving figitumumab compared to chemotherapy alone included pneumonia (6% vs 4%), hyperglycemia (3% vs <1%), asthenia (3% vs 1%), and dehydration (4% vs 1%). The etiologies of the 17 treatment-related deaths in patients treated with figitumumab included pulmonary hemorrhage, pneumonia, septic shock, hypovolemic shock, sepsis in a neutropenic patient, renal failure, hemorrhage, and etiologies listed as cardiorespiratory arrest, toxicity to various agents, and decrease of performance status (46).

The combination of EGFR plus IGF-1R inhibition has been tested in a cohort of unselected patients with lung adenocarcinoma or squamous cell carcinoma, but there was no improvement in PFS or OS compared to treatment with EGFR inhibition alone. Importantly, in this study less than 5% of patients had an EGFR mutation, as it was proposed that based on preclinical models IGF-1R and EGFR crosstalk was a key mechanism of tumorigenesis and resistance to isolated EGFR inhibition in patients with NSCLC independent of EGFR mutation status (49).

Other therapeutic agents which target the IGF-1R pathway

The growing appreciation of INSR mediated signaling in the IGF pathway has led to two novel strategies to target the IGF-1R pathway in patients with advanced breast cancer, sarcoma, and NSCLC: combined IGF-1R and insulin receptor inhibition (8) and therapeutic antibodies directed against the IGF-1 and IGF-2 ligands (50, 51).

Based on antitumor activity demonstrated in preclinical models in several tumor types, OSI-906 (linsitinib), an oral small-molecule tyrosine kinase inhibitor of IGF-1R and INSR, has been evaluated in 86 patients with advanced, treatment refractory solid tumors. When patients were treated with OSI-906 monotherapy the overall disease stabilization rate was 36% and one patient with melanoma achieved a PR (8). Recently completed phase II trials have evaluated OSI-906 combination therapies with paclitaxel in patients with recurrent ovarian cancer (NCT00889382) and with erlotinib in patients with metastatic EGFR mutant NSCLC (NCT01221077). Results from these trials are pending.

MEDI-573, a mAb to both IGF-1 and IGF-2, has demonstrated the ability to suppress IGF signaling through both IGF-1R and INSR-A without affecting normal INSR-B mediated signaling in cancer cell lines, leading to its use in an early clinical trial in patients with advanced, heavily pretreated solid tumors (50). In this trial, the disease stabilization rate was 30% with no PRs or CRs observed. Based on preclinical studies showing increased INSR-A:INSR-B mRNA ratios in tumor tissue from patients with hormone receptor positive, ERBB2 negative tumors, there is now a phase I/II clinical trial underway assessing the impact of MEDI-573 combined with hormonal therapy in this subset of breast cancer patients (NCT01446159) (50).

A second mAb to both IGF-1 and IGF-2, BI 836845, has been tested in phase I clinical trials involving 81 patients with advanced solid tumors (52, 53). The results have demonstrated tolerability and two patients have experienced a partial response, resulting in additional ongoing clinical trials involving the combination of BI 836845 with afatinib in patients with EGFR-mutant NSCLC in East Asia (NCT02191891) and in combination with everolimus and exemestane in patients with ER+ breast cancer (NCT02123823).

Challenges to clinical applications

The most pressing and as yet undefined challenge to the appropriate clinical application of IGF-1R pathway blockade is the identification of predictive markers that are able to identify patients likely to respond to this therapeutic strategy. As the clinical trials data shows, there are some treatment combinations that have shown disease stabilization rates of one-quarter to one-half of patients, and there has been some intriguing antitumor activity, especially in patients with sarcoma. However, what is now critically needed is development of predictive biomarkers that can guide future clinical trials in applying this therapeutic strategy to the patient populations most likely to benefit.

The identification of predictive biomarkers can be divided into four main categories which have seen varying levels of success: tumor expression of IGF-1R and its pathway components, serum IGF ligand levels, assessment of alternate pathway activation, and attempts at identifying specific molecular signatures of IGF-1R pathway dependence.

Pretreatment IGF-1R expression as assessed by immunohistochemistry has not consistently been correlated with disease control in heterogeneous groups of patients treated with anti-IGF-1R mAbs (32, 35, 44). It is important to note that when tumor expression of a target of a therapeutic agent does not correlate with response, there are many possible etiologies of false negative signals including sampling bias, variability in sample handling, limited assay sensitivity and specificity, and tumor mutations between when a sample is obtained and when treatment is administered (32).

In the case of IGF ligand assessments, serum ligand levels have consistently demonstrated predictive value in patients with sarcoma and NSCLC, although it must be noted that the degree of correlation between IGF ligand levels in the serum versus in the tumor microenvironment is unknown. In two clinical trials involving patients with sarcoma treated with IGF-1R inhibitor monotherapy, elevated pretreatment and on-treatment serum IGF-1 levels were associated with improved OS (40, 41). In patients with NSCLC, both a phase I (47) and a phase III clinical trial (46) have demonstrated improved disease control and OS in patients with elevated pre-treatment serum total IGF-1 (46) and greater elevations in serum IGF-1 when treated with figitumumab plus carboplatin/paclitaxel (46, 47). In contrast to serum IGF-1 levels, pretreatment levels and on-treatment changes in serum IGFBP3 have not been associated with disease control (5), combination IGF-1R and MTOR inhibition (19, 37), or IGF-1R inhibition in combination with cytotoxic chemotherapy (18, 47).

The assessment of alternative pathway activation mediating resistance to IGF-1R targeted therapies was the impetus for the combination trials described above. However, the interpretation of the heterogeneous responses to combination therapy necessitate a better understanding of the crosstalk between the IGF-1R pathway and other important signaling molecules such as EGFR, SRC, and ER (54–56) and downstream molecules such as MTOR, PI3K, and AKT1, which have been shown to mediate IGF-1R resistance in preclinical models (57).

Finally, specific gene expression profiles associated with IGF-1R sensitivity or resistance have been identified in models of breast cancer and Ewing’s sarcoma (58–60). This characteristic IGF-1-dependent gene expression profile includes upregulation of transcriptional targets of ER, MAPK3, MAPK1, and components of the PI3K-AKT1-MTOR pathway (58). The assessment of these molecular signatures and alternative pathways mediating IGF-1R resistance within the context of the significant clinical trials data described above is an important next step in improving the patient-specific application of IGF-1R targeting therapies (61).

Conclusions

In conclusion, the IGF-1R pathway is important in the development and maintenance of many different types of malignancies. Drug development targeting this pathway has taken unique routes by different tumor types, from preferential combination therapy in the case of patients with breast cancer to impressive antitumor efficacy in patients with sarcoma treated with anti-IGF-1R monotherapy to a negative phase III trial in combination with cytotoxic chemotherapy in patients with NSCLC. The most pressing needs for the future development of this therapeutic strategy are identifying biomarkers of response by applying a bedside to bench approach with the existing clinical trials data, including an in depth analysis of tumor samples from patients who have responded to IGF-1R directed therapies. These critical analyses will serve as the foundation to guide the most appropriate application of IGF-1R blockade in the clinic.

Acknowledgments

Grant Support

C.M. Lovly is supported in part by the NIH and the NCI under award numbers R01CA121210 and P01CA129243, a Damon Runyon Clinical Investigator Award, and a LUNGevity Career Development Award.

Footnotes

Disclosure of Potential Conflicts of Interest

C.M. Lovly reports receiving commercial research grants from AstraZeneca and Novartis, and is a consultant/advisory board member for ARIAD Pharmaceuticals, Genoptix, Harrison and Star, Novartis, and Sequenom. No potential conflicts of interest were disclosed by the other author.

Disclaimer

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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