Targeting the IGF1R signaling pathway: Clinical implications

Proc Amer Assoc Cancer Res, Volume 46, 2005 SY05-1 The insulin-like growth factor receptor I (IGF-1R) is a cell surface associated tyrosine kinase growth factor receptor that plays a role in cell growth, migration and survival. IGF-1R is activated by IGF-1 and IGF-2, which upon binding to the extracellular domain induce a conformation shift resulting in the activation of kinase activity and the recruitment and phosphorylation of intracellular substrates. IGF-1R has been studied extensively over the years and has been implicated in the progression of human cancers. IGF-1R expression or enhanced activation has been demonstrated in many cancer types, which include breast, colon, melanoma and prostate. Accumulating epidemiological data have linked increased IGF-1 serum levels as a risk factor for breast, colorectal and lung cancers. In vitro and in vivo studies have demonstrated that activation of IGF-1R results in an increase in cell growth and transformation and induces tumor formation in xenografts models. Fibroblasts devoid of IGF-1R are unable to be transformed by some but not all oncogenes, and transformation can be resurrected by restored expression of IGF-1R. Blockade of IGF-1R activity by antisense RNA, siRNA, dominant negative IGF-1R, small molecule kinase inhibitors and anti-IGF1R antibodies results in the inhibition of cellular transformation, tumor growth and an increase in apoptosis. While the link between IGF1R and cancer has been established for nearly two decades, the emergence of IGF-1R inhibitors into clinical oncology has just recently been achieved. Several companies whose approaches include antibodies or small molecule kinase inhibitors have entered or are soon to enter phase I studies. Anti-IGF-1R antibodies are exquisitely selective inhibitors that block receptor function by inducing the rapid internalization and down regulation of the receptor. The long half-life of antibodies provides the opportunity to inhibit receptor function for days to weeks with a single administration and decreases the potential of Cmax related toxicities. The role of specific antibody isotypes such as IgG1 vs. IgG2 vs. IgG4 in engaging immune effector function and enhancing efficacy or toxicity is yet to be determined. Small molecule kinase inhibitors have a different set of upsides and challenges. ATP-competitive IGF-1R small molecule kinase inhibitors may suffer from a lack of selectivity, because they bind at a site well conserved among hundreds of kinases. This is especially the case with the IGF-1R and IR whose catalytic domains are 100 % identical. The pharmacology of administering kinase inhibitors lends itself to a time period where the Cmax concentrations may be sufficient to inhibit off-target kinases, even if the compound is 100-fold selective. Nevertheless, small molecular inhibitors have an advantage over antibodies because of the ability to control the duration of drug exposure more precisely. With respect to the IR, the obvious clinical concern would be an induced diabetic response, which may be circumvented by discontinuous therapy. Interestingly, inhibiting the IR may have upside with regards to inhibiting cancer progression. The IR has been shown to be up-regulated in cancer cells and can form a heterodimer complex with IGF-1R. This heterodimer complex can be activated by both IGF-1 and IGF-2. Unlike IGF-1, IGF2 can also activate the IR with high affinity and induce a proliferative response. Thus, the contribution of IR and the IGF-1R/IR complex in driving tumor progression is unknown and may be best elucidated by the use of small molecule inhibitors that inhibit both kinase receptors. CP-751,871 is human IgG2 anti-IGF-1R monoclonal antibody that has progressed into phase I clinical trials in patients with multiple myeloma. The mechanism of action of this agent is to both block IGF-1 and IGF-2 binding and induce a rapid internalization of IGF-1R with a Kd of ∼1nM. Administration of CP-751,871 to nude mice bearing tumors from a variety of tissue types resulted in the inhibition of tumor growth. Antibody doses and subsequent systemic exposures that inhibited tumor growth were equivalent to the concentration of drug required to down regulate IGF-1R within the tumor. Enhanced anti-tumor efficacy in these models was demonstrated when CP-751,871 was used in combination with other anti-cancer therapies including adriamycin, 5-FU, Tamoxifen and erbB inhibitors. In the clinical trials of CP-751,871 in multiple myeloma patients, a mechanistic biomarker is being incorporated into the clinical plan. The goal would be to correlate the concentration of CP-751,871 in the blood with the degree of IGF-1R depletion. These data can provide evidence as to whether or not the drug is working in a human, and what level of receptor modulation is linked to efficacy. This approach was validated by pre-clinical studies where the concentration of CP-751,871 required to down regulate 50% of IGF-1R on PBLs derived from cancer patients was 0.3 nM. One of the major mechanisms that IGF-1R may promote tumor growth is to provide an enhanced survival signal. This is substantiated by the observation that addition of IGF-1 to cell culture experiments decreases the toxicity of chemotherapy, and conversely, blockade of IGF-1R signaling enhances the efficacy of chemotherapy. Drug resistance is a phenomenon that plaques the successes of cancer therapy today. A common mechanism for drug resistance involves efflux mechanisms such as MDR and BCRP membrane proteins that pump drugs out of cells. Other mechanisms of resistance have been uncovered. Gleevec resistance was found associated to mutations in the ATP binding pocket decreasing the affinity of drug for the active site. The mechanism of resistance to the anti-erbB2 antibody Herceptin, while not fully defined, is likely to involve events distinct from membrane pumps and kinase domain mutations because the antibody targets the extracellular domain of ErbB2. Efforts to better understand how an antibody therapeutic such as Herceptin could induce resistance were initiated using the breast carcinoma xenograft model, BT-474. BT-474 tumor-bearing mice were exposed to weekly doses of Herceptin over a period of months. A cell line was generated (BT-474-HR) from these resistant tumors and was found to be resistant to Herceptin in proliferation assays in vitro and growth in vivo. Western blot analysis demonstrated a decreased level of erbB2 and EGFR expression, a modest increase in erbB3 and erbB4 expression and a large increase in IGF-1R expression. In addition, erbB2 gene amplification was lost in the BT-474-HR cell line as compared to the parental. These data support the hypothesis that IGF-1R may be playing a role in how cancer patients develop Herceptin resistance. Efforts are underway to better understand the consequences of these altered expression patterns, the role of IGF-1R in drug resistance and how to best use these data to develop novel therapeutic strategies.