In this issue of ONCOLOGY, Golan and Javle present a timely review of the current status of the insulin growth factor-1 receptor (IGF-1R) signaling pathway as a therapeutic target, with a specific focus on gastrointestinal (GI) cancers. Over the past few years, this has been an especially active area of clinical research, with over 30 agents having been brought into early-phase clinical studies.
There are several lines of evidence to support the view that the IGF-1R pathway is an important target for cancer therapy.[1-3] First, expression of IGF-1R is required by several cellular and viral oncogenes for malignant transformation. Second, epidemiological and case control studies have demonstrated that insulin resistance, as manifested by hyperinsulinemia, is associated with an increased risk for a number of solid tumors, including cancers of the breast, lung, prostate, colon, and kidney. Third, increased levels of circulating IGF-1 have been associated with an increased risk of breast, prostate, and colorectal cancer, while increased levels of IGF-2 have been identified in patients with ovarian cancer and colorectal cancer. Fourth, increased expression of IGF-1R has been observed in a wide range of human cancers, such as breast, prostate, colorectal, liver, and melanoma. Fifth, activation of IGF-1R signaling leads to downstream activation of a number of important cellular signaling pathways that mediate proliferation, survival, invasion/metastasis, and angiogenesis, all of which contribute to the malignant phenotype. Sixth, this pathway displays cross-talk with several important signaling pathways, such as EGFR (epidermal growth factor receptor) and erb-B2, as well as hormone receptors. Thus, IGF-1R signaling may confer resistance to chemotherapy, radiation therapy, targeted agents, and hormonal therapy.
Several approaches have been taken to inhibiting the IGF-1R signaling pathway,[4-6] and this topic is nicely reviewed by Golan and Javle. One strategy is to reduce the levels of the IGF ligands, either through inhibition of the release of growth hormone from the pituitary gland or by neutralizing antibodies that specifically target the IGF-1 and IGF-2 ligands. Another approach, which has been the major focus of drug development to date, has been to target IGF-1R through the use of monoclonal antibodies or tyrosine kinase inhibitors. Monoclonal antibodies directed against the external cell surface domain of IGF-1R interfere with ligand binding, which prevents ligand-induced activation of IGF-1 signaling. In addition, receptor internalization is induced, resulting in receptor degradation by endocytosis. The potential advantage of monoclonal antibodies is that they can bind to both IGF-1R and IGF-1/IR hybrid receptors and have no affinity for insulin receptors (IRs). Thus, antibodies would not be expected to affect insulin and IGF-2 signaling, which has been viewed as an attractive feature of this approach. However, there is growing evidence to suggest that individual tumors may rely on IR signaling for growth and proliferation, and in this setting, monoclonal antibodies directed specifically against IGF-1R would not be expected to confer clinical benefit.
In general, treatment with IGF-1R–directed monoclonal antibodies has been relatively well-tolerated; the main side effects have been hyperglycemia, fatigue, and thrombocytopenia. Clinical activity has been observed in a broad range of tumor types, including Ewing sarcoma, rhabdomyosarcoma, osteosarcoma, non–small-cell lung cancer, neuroendocrine tumors, and prostate cancer. With respect to GI tumors, activity has been reported in colorectal cancer and pancreatic cancer. Of note, the immunoglobulin G1 (IgG1) antibody AMG 479 (ganitumab) has shown promising clinical activity in a randomized phase II trial in the treatment of advanced pancreatic cancer when combined with gemcitabine(Drug information on gemcitabine) (Gemzar); combination therapy with AMG 479 and gemcitabine resulted in improved median progression-free and overall survival compared with single-agent gemcitabine. Based on these findings, a randomized phase III trial is now underway to confirm the potential clinical activity of this IGF-1R antibody. While the results of this study are eagerly awaited, one word of caution: no specific strategy was included in the study design to enrich for patients who would respond to this IGF-1R antibody.
Small molecular inhibitors inhibit IGF-1R activation by binding to and blocking the catalytic domain of the associated tyrosine kinase. Given the relatively high homology between IGF-1R and IR, one of the potential advantages of these small molecules is that they might display greater potency, especially in those tumors driven by both signaling pathways or in those driven in large part by the IR pathway. However, this enhanced activity may be at the expense of increased toxicity, especially as it relates to the diabetogenic response and the development of hyperglycemia. Several small molecules have entered clinical investigations; the main GI tumor types that this research has focused on, to date, include advanced pancreatic cancer and hepatocellular cancer.
What are the challenges moving forward with future development of IGF-1R inhibitors? As with other targeted therapies, perhaps the highest priority is to develop biomarkers that can identify the subset of patients who would benefit most from drugs that target IGF-1R. While the major focus has been on the development of positive predictive biomarkers, it would also be quite appropriate to identify potential negative predictive biomarkers, since negative biomarkers would eliminate patients who would not derive benefit from this approach. There is emerging data to suggest that low expression of IGF-1R in tumors may identify patients who would not derive clinical benefit from small molecule inhibitors directed against IGF-1R and IR. In support of this concept, it has been suggested that IGF-1R overexpression may be necessary but insufficient to accurately predict sensitivity to the h10H5 humanized monoclonal antibody developed by Genentech. The Genentech researchers, along with others, have shown that expression of ligands IGF-1 and IGF-2, levels of IGF binding proteins (IGFBPs), and the adapter proteins IRS1 and IRS2 may also play a key role in patient selection. In addition, much research is being done to develop gene expression signatures as well as proteomic signatures predictive of response. Obviously, another significant challenge rests with the types of methodologies used for biomarker development. It will be critically important to develop and integrate into the clinical setting methods that are sensitive, quantitative, and easily reproducible. In addition to identifying predictive biomarkers that will facilitate patient selection, another important focus has been on the development of potential pharmacodynamic biomarkers that can determine whether a given patient being treated with an IGF-1R inhibitor compound is indeed deriving clinical benefit. Because follow-up tumor biopsies are simply not practical in the large majority of patients treated, significant efforts are being directed at the use of surrogate tissues, such as peripheral blood mononuclear cells and circulating tumor cells.
While there are already clinical data demonstrating single-agent activity, the most likely scenario will be that therapies directed against IGF-1R will find their greatest utility when combined with either conventional cytotoxic chemotherapy or other targeted agents. The usual strategy of combining an anti–IGF-1R agent with drug X is clearly unacceptable and doomed for failure. The challenge will be to conduct the appropriate pre-clinical in vitro and in vivo studies to document biological activity of these combination strategies and to then extend this work into early-phase clinical studies with appropriate patient enrichment/selection as well as incorporation of key pharmacodynamics biomarker studies. Important dose-finding and sequencing studies will also be required to identify the optimal combination strategy.
Finally, cellular drug resistance represents a major issue that needs to be considered in the development of agents that target IGF-1R signaling. Just as cancers can quickly develop resistance to chemotherapy and targeted agents, given their inherent genetic instability, resistance to IGF-1R inhibitors can quickly develop through activation of downstream signaling processes and/or through activation of alternative, vertical signaling pathways. Future pre-clinical and clinical studies will need to begin to identify the potential molecular mechanisms by which drug resistance develops.
In summary, the IGF-1R signaling pathway represents a rational target for cancer therapy, with evidence for clinical activity in several GI cancers. Moving forward, the success of the drug development program in identifying clinically active inhibitor compounds will depend on the incorporation of biomarker-guided patient selection, on development of certain key pharmacodynamic biomarkers, and on careful evaluation of combination therapies. This is a significant challenge that will require the collaborative interactions of basic scientists, clinical and translational investigators, and key individuals from industry and the regulatory authorities.
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.