Targeting the Insulin Growth Factor Pathway in Gastrointestinal Cancers
Targeting the Insulin Growth Factor Pathway in Gastrointestinal Cancers
Abstract: Insulin-like growth factor 1 (IGF-1)–directed therapy is currently at a crossroads. After decades of research, several agents targeting the IGF pathway are now in clinical trials. One recent phase III trial of the IGF-1R inhibitor figitumumab in patients with non–small-cell lung cancer was discontinued after an interim analysis showed no survival improvement. Clinical trials for patients with sarcoma have demonstrated impressive anti-tumor activity in cases where the IGF-1 pathway is activated, such as in Ewing sarcoma; however, acquired resistance has been common. Recently, randomized phase II trials combining IGF-1R with epidermal grown factor receptor (EGFR) inhibition in colorectal cancer have been completed. Preclinical studies have indicated that several biomarkers may have potential predictive value. Studies of IGF-1R inhibitors in gastrointestinal cancers are currently ongoing in pancreatic, gastroesophageal, hepatocellular, and colorectal cancers. A critical analysis of prior work in this field and a rational strategy for maximizing success on the basis of biomarker use are necessary.
IGF-1R Targeting and Cancer
The insulin-like growth factor 1 (IGF-1) pathway is a key regulatory pathway that has been conserved in the evolutionary process and is responsible for cellular proliferation and survival in response to exogenous stimuli. This role has particular relevance in cancer where cellular growth and survival despite apoptotic stimuli promote carcinogenesis and metastatic spread. Targeted inhibitors of the IGF-1 pathway, both monoclonal antibodies and small-molecule tyrosine kinase inhibitors, are currently under investigation in clinical trials for a diverse spectrum of cancers. This review highlights the current status of the research in this field with a specific focus on gastrointestinal cancers.
The IGF-1 receptor (IGF-1R) is structurally similar to the insulin receptor (IR), with an 85% protein-sequence identity between the kinase domains of these receptors.[2,3] Both are transmembrane receptors with an extracellular, ligand-binding subunit and an intracellular α subunit, which has tyrosine kinase activity. In addition, the IGF-1 pathway consists of its ligands (IGF-1 and IGF-2), six binding proteins (IGFBP1-6) that limit the free or bioavailable ligand, its intracellular signaling proteins (insulin receptor substrates 1 and 2 (IRS-1 and IRS-2), and the downstream effector networks (the phosphatidylinositol 3-kinase [PI 3-kinase]/Akt/mTOR and the ras-raf-MAP kinase pathways).
IGF-1 is produced mainly in the liver and is controlled by human growth hormone (GH), which is secreted by the somatotrophic cells of the anterior pituitary. The latter, in turn, are regulated by hypothalamic GH-releasing hormone and somatostatin. IGF-2 is also produced in the liver, and both these ligands activate IGF-1R. However, in the case of neoplastic transformation, cancer cells acquire autocrine or paracrine capacity for ligand production and may no longer be dependent on circulating ligand levels. Bergmann et al analyzed 12 pancreatic cancer specimens and noted a several-fold increase in IGF-1 mRNA transcripts in pancreatic cancer cells compared with normal pancreas or pancreatic cancer cell lines, suggesting that autocrine and paracrine IGF-1 production plays an important role in driving the IGF-1R. Activation of IGF-1R results in the phosphorylation of IRS-1 and downstream effector proteins of the PI 3-kinase/Akt, mTOR, and S6 kinase pathways. IGF-2R, on the other hand, has no intracellular tyrosine kinase domain and therefore does not have a signaling role. Increased expression of IGF-2 in colon cancer (which results from the loss of imprinting [epigenetic silencing of one allele]) compared with the expression in normal colonic mucosa has underscored the role of IGF-2 in tumor progression. The bioavailability of IGFs is limited by the six IGFBPs, of which IGFBP-3 has the greatest binding capacity. In the serum, the IGFs are bound to IGFBPs, which protect the ligands from proteolysis and thereby prolong their half-lives. It is believed that high levels of IGFBP-3 decrease the available IGF-1; however, the relationship is more complex and context-dependant. In certain cases, IGFBPs can actually increase IGF-1 signaling or can exert their effects in an IGF-1–independent fashion.
The role of the IGF-1 pathway in cancer development
Several mechanisms resulting from IGF-1R activation and signaling underlie oncogenesis and cancer progression. IGF-1R has several key features that suggest its role in regulating tumor growth; these include potent anti-apoptotic and mitogenic capacity, and a role in angiogenesis, invasion, and metastasis. Support for a role for IGF-1R in oncogenic transformation is provided by the fact that IGF-1R–null fibroblasts do not undergo neoplastic transformation when exposed to cellular and viral oncogenes. IGF-IR is not an oncogene; it is very rarely mutated in cancer. However, its expression is a requirement for neoplastic transformation by oncogenes such as K-ras. IGF-1R–directed monoclonal antibodies and small molecules inhibit tumor growth and metastasis in xenograft models.[10,11] Recent preclinical studies have highlighted the role of the IGF-1 ligand in tumor invasiveness and metastases. The levels of circulating IGF-1 in liver-specific IGF-1 gene-deleted (LID) mice are 75% lower than the levels in control mice; these lower levels result in smaller primary colon cancers and hepatic metastases.
Human epidemiological studies
Several prospective studies have investigated the relationship between IGF-1 levels and the risk of developing cancer. A prospective nested case-control study within the Physicians’ Health Study reported a strong positive association between IGF-1 levels and prostate cancer risk. Men in the highest quartile of IGF-1 levels had a relative risk of 4.3 (95% confidence interval [CI], 1.8 to 10.6) compared with men in the lowest quartile. Analysis of colon cancer risk in the Nurses’ and Physicians’ Health Studies indicated a high cancer risk in both women and men with the highest IGF-1 values. High levels of circulating IGF-1 and low levels of IGFBP-3 were independently associated with an elevated risk of colorectal cancer (CRC).[15,16] Several additional studies have been summarized in a large meta-analysis: in five studies in CRC, there was a positive association between elevated levels of circulating IGF-1 and CRC risk, with an odds ratio (OR) of 1.58 (95% CI, 1.11 to 2.27). On a multivariate meta-regression analysis, however, this association was of borderline statistical significance (P = .09). In the European Prospective Investigation into Cancer and Nutrition (EPIC) study, however, serum concentrations of IGF-1 and IGFBP-3 showed no associations with CRC risk. In another recently published meta-analysis, a modest positive association was reported between serum IGF-1 and CRC risk overall (relative risk = 1.07 for 1 standard deviation increase in IGF-I). Genomic variations in the form of single nucleotide polymorphisms (SNPs) of the IGF pathway may also be associated with increased risk of gastrointestinal cancers. These are summarized in Table 1 and underscore the importance of this pathway in gastrointestinal malignancies.
Agents That Target IGF-1R
Monoclonal antibodies and small-molecule tyrosine kinase inhibitors that target IGF-1R are currently in phase II or III clinical trials for a variety of cancers. Other experimental, antagonistic options include antisense oligonucleotides, IGFBPs, and kinase-negative mutants. These agents are designed to block the expression and activation of IGF-1R and the ligand-receptor interactions. Over 30 agents have been developed for clinical investigation, and to our knowledge,12 are in clinical trials. The relevant trials in gastrointestinal cancers are shown in Table 2.
The antibodies block the ligand-receptor interaction, internalize the receptor, and cause the degradation of the receptor, while the tyrosine kinase inhibitors block activation of the receptor (tyrosine kinase activity) but not its expression. The present agents differ in their ability to target the insulin receptor (IR). Most tyrosine kinase inhibitors have a broader range and target IGF-1R, IR, and the hybrid receptor IGF-1R/IR. The antibodies do not generally bind to IR; however, figitumumab (CP-751,871) and Sch717454 may be able to block insulin signaling by binding to the hybrid receptor. Therefore, toxicity in the form of hyperglycemia is expected to differ between the antibodies and the tyrosine kinase inhibitors. Other secondary effects of IGF-1R inhibition include the elevation of IGF-1, growth hormone (GH), and insulin levels. This is particularly relevant in pancreatic and neuroendocrine cancers, in which glucose intolerance is common. In clinical trials, however, these effects have not led to serious toxicities, and the hyperglycemia can be easily managed with oral hypoglycemics like metformin or by insulin administration. Hyperinsulinemia resulting from IGF-1R inhibition raises theoretical concerns, since increased cancer risk and poor prognosis have been well documented in cancer patients with obesity and hyperinsulinemia. However, to date there is no objective evidence of a deleterious effect in the cancers treated with IGF-1R inhibitors.
The monoclonal antibodies currently in clinical trials are either fully human or humanized, and hypersensitivity reactions are exceedingly rare. However, most antibodies are of the immunoglobulin G1 (IgG1) class, making them liable to induce antibody-dependant, cell-mediated cytotoxicity (ADCC) and complement fixation (the one exception is figitumumab, which is an IgG2 antibody). As a result, thrombocytopenia is more likely with the IgG1 antibodies. These toxicities have to be considered when planning combination therapies with cytotoxic agents.