Targeting the IGF Receptor as Treatment for Cancer (2007)

CN01-02 The insulin-like growth factor (IGF) axis is an important regulator of normal growth and development. IGFs bind to and activate the type 1 IGF receptor (IGF1R), a tetrameric receptor tyrosine kinase (RTK) composed of two extracellular alpha subunits and two transmembrane beta subunits with tyrosine kinase activity. IGF1R activation triggers intracellular signaling cascades including the PI3K-Akt and RAS-RAF-ERK pathways. Depending on the cell/tissue context, this can lead to proliferation, differentiation, transformation, cell motility and cell survival via protection from apoptosis. The IGF1R is closely related to the insulin receptor (IR), which exists in two isoforms: the classical IR (IR-B), required for glucose uptake, and the exon 11- isoform (IR-A), which mediates an anti-apoptotic response to IGF2.  Over the last 10-15 years there has been increasing recognition of the critical role of IGFs in tumour biology, and the frequency of aberrant expression of components of the IGF axis. IGF1R over-expression has been found in a range of tumour types, and is of adverse prognostic significance in gastric, renal and lung cancers. Tumours may also express IR-A and IGF1R:IR hybrid receptors, which behave like authentic IGF1Rs. In addition, high/normal levels of circulating IGF1 correlate with an increased risk of development of cancers of the prostate, breast and colon, probably by favouring survival of early lesions that would otherwise remain clinically occult.  The IGF1R is required for transformation by most oncogenes, and its growth/survival function is extremely important for the anchorage-independent mode of growth required for tumour formation, in which cells must survive apoptosis induced by loss of anchorage. IGFs also protect against apoptosis induced by adverse factors in the tumour microenvironment, including hypoxia and nutrient starvation, and by various forms of cancer therapy including cytotoxic drugs and ionising radiation. Finally IGF signaling regulates tumour cell adhesion and motility, and induces expression of proteins including matrix metalloproteinases, so influencing the ability of cancer cells to invade and metastasise.  The IGF1R is now widely recognised as an attractive target for cancer treatment. In fact an IGF1R antibody was the first RTK antibody shown to have anticancer activity in vivo. However it must be acknowledged that the IGF1R is not an ideal treatment target, because of its virtually ubiquitous expression, and close homology with the IR. Because of these factors, clinical development of IGF1R inhibitors has lagged behind the targeting of other RTKs including the epidermal growth factor receptor (EGFR) and Her2. The kinase domains of the IGF1R and IR are 84% homologous, with 100% homology in the ATP binding cleft. Therefore IGF1R tyrosine kinase inhibitors (TKIs) that compete for ATP binding also inhibit the IR to some extent, whereas non-ATP antagonists show greater specificity. ATP antagonist IGF1R inhibitors have been designed by Novartis and Bristol-Myers-Squibb; the former shows selective IGF1R inhibition in intact cells, while the latter also inhibits the IR. ATP non-competitive IGF1R TKIs include picropodophyllin, a non-toxic stereoisomer of podophylotoxin that inhibits phosphorylation of the IGF1R kinase activation loop, and catechol bioisosteres of the tyrphostin AG 538, which block substrate binding. Both ATP -competitive and -non-competitive inhibitors block IGF signaling, inhibit proliferation, and induce apoptosis in a wide range of tumour cell types. In vivo, these agents show clear evidence of anti-cancer activity, notably in models of myeloma and tumours engineered to be IGF1R-dependent. Only one IGF1R TKI has thus far reached the clinic: an ATP non-competitive IGF1R inhibitor, INSM18 (Insmed), which also inhibits Her2, has undergone Phase I-II evaluation in patients with advanced prostate cancer.  IGF1R antibodies block IGF signaling via inhibition of ligand binding and induction of IGF1R internalisation and degradation. Although they show specific IGF1R binding, IGF1R antibodies can inhibit insulin signaling, by downregulating IRs involved in the formation of IGF1R:IR hybrids, or adjacent to IGF1R in membrane lipid rafts. IGF1R antibodies have shown in vivo antitumour activity in a range of tumour models including prostate and breast cancer xenografts. At the present time there are six different human IGF1R monoclonal antibodies in early phase clinical trials in patients with solid tumours and multiple myeloma. These are CP-751,871 (Pfizer), AMG479 (Amgen), IMC-A12 (Imclone), MK0646 (Merck), R1507 (Roche) and AVE1642 (Sanofi-Aventis, licensed from Immunogen). Thus far these new agents appear to be well-tolerated; although some patients have developed hyperglycaemia, there is no evidence of severe toxicity. In the longer term it will be important to evaluate any toxicity to IGF-dependent tissues including nerves and muscle. At this early stage there is only limited evidence of single agent activity, with the report of objective responses to AMG 479, and disease stabilisation in other trials. Given its role in normal growth, its homology with the IR, and the effects shown in preclinical testing, the prediction would have been that IGF1R blockade would have striking single agent activity, and severe toxicity. At this stage neither prediction has been fulfilled.  Several issues will need to be addressed as clinical evaluation proceeds. Firstly, it will be important to identify features that correlate with sensitivity or resistance to IGF1R blockade. While RTK expression levels and kinase domain mutations are known to influence sensitivity to blockade of Her2 and EGFR respectively, there is no evidence that these factors affect sensitivity to IGF1R inhibitors. It is theoretically possible that tumour IR-A could mediate resistance to IGF1R blockade, but this is unlikely given that IGF1R TKIs and blocking antibodies can induce IR inhibition or downregulation. Factors that may indicate dependency on IGF signaling include autocrine production of IGFs, and ligand-sensitive phosphorylation of IGF effectors including Akt. We have used the approach of IGF1R gene silencing to investigate molecular correlates of sensitivity to IGF1R targeting, and found that IGF1R depletion is capable of blocking tumour cell survival, even in cells harbouring mutations that activate key intermediates in the PI3K-Akt or RAS-RAF-ERK pathways downstream of the IGF1R. Given the frequency of these mutations in human tumours, these findings are encouraging for the approach of IGF1R blockade.  A second, and related, issue, is how best to use this approach in combination with other treatments. IGFs are known to protect against apoptosis induced by cytotoxic drugs, and IGF1R inhibition or depletion enhances chemosensitivity in vitro and in vivo. Indeed the antibody CP-751,871 is already showing promise in combination with chemotherapy, in patients with prostate and lung cancer. The ability of the IGF axis to influence chemosensitivity may relate not only to its known function in regulating apoptosis, but also to direct involvement in the cellular response to DNA damage. Our current research aims to understand the molecular links between IGF signaling and DNA repair, information that may guide selection of cytotoxic drugs to combine with IGF1R inhibitors. There is also substantial evidence to support the combination of IGF1R inhibition with other biological treatments. It is naive to suppose that inhibition of one RTK will have no effects on other signaling systems: we and others have found that IGF1R depletion induces enhanced signaling via the EGFR and IR that could mediate resistance to IGF1R inhibition. Furthermore, sensitivity to IGF1R blockade is reported to correlate with levels of expression of signaling intermediates activated by the EGFR. We have detected IGF1R:EGFR complexes in human breast and lung cancer cells and clinical samples of breast cancer, and similar complexes have been observed in lung tumours from patients resistant to EGFR TKI. Indeed the IGF axis is increasingly recognised as a candidate mediator of resistance to inhibition of RTKs including the EGFR and Her2, and of downstream effectors including mTOR. Co-targeting of the IGF1R:EGFR and IGF1R:Her2 has been shown to be synergistic in the experimental setting, and it will be logical to evaluate clinically the combination of IGF1R blockade with inhibitors of these kinases, aiming to delay or prevent the development of resistance to blockade of individual kinases/pathways.  In summary, initial clinical assessment of IGF1R blockade suggests that toxicity is not a major problem, but that single-agent activity is limited. This impression contrasts with the ability of IGF1R blockade to induce significant tumour growth inhibition in the experimental setting. This discrepancy may reflect in part the use of animal models designed to be IGF-responsive, and the fact that IGF1R blockade generally causes tumour growth delay rather than regression in vivo. There is experimental support for the concept that even in the absence of effects on the growth of primary tumours, IGF1R inhibition may suppress tumour invasion and metastasis. This is a property that is difficult to test in patients with advanced malignancy. Whether or not IGF1R blockade proves to have objective activity in patients with metastatic cancer, there is strong justification for evaluation in the adjuvant setting, as monotherapy or more likely in combination with chemotherapy. Thus the next few years will be an exciting time for IGF research, as we determine how to exploit most effectively the potential benefits of this new therapeutic approach.