Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment.

Abstract

The ErbB receptors and their cognate ligands that belong to the epidermal growth factor (EGF) family of peptides are involved in the pathogenesis of different types of carcinomas. In fact, the ErbB receptors and the EGF-like growth factors are frequently expressed in human tumors. These proteins form a complex system that regulates the proliferation and the survival of cancer cells. Therefore, ErbB receptors and their ligands might represent suitable targets for novel therapeutic approaches in human carcinomas. In this regard, different target-based agents that are directed against the ErbB receptors have been developed in the past two decades. One of these compounds, the humanized anti-ErbB-2 monoclonal antibody trastuzumab has been approved for the treatment of patients with metastatic breast cancer. The anti-EGF receptor (EGFR) antibody C225, as well as EGFR tyrosine kinase inhibitors ZD1839 and OSI-774 are currently in phase III clinical development. Several other ErbB tyrosine kinase inhibitors are in phase I/II studies. These compounds have generally been shown to have an acceptable toxicity profile and promising anti-tumor activity in heavily pretreated patients. The mechanisms of action of these compounds, as well as the potential therapeutic strategies to improve their efficacy are discussed in this review with particular regard to the combinations of anti-ErbB agents with cytotoxic drugs, or combinations of different ErbB-targeting agents.

Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells

“…In particular, we have shown that blockade of both tyrosine kinases causes a prolonged inhibition of MAPK and AKT activation as compared with inhibition of a single receptor. Both these pathways are involved in the intrinsic and acquired resistance of breast cancer cells to anti-EGFR and anti-ErbB-2 drugs [26,31,32]. Interestingly, our findings show that following treatment with trastuzumab an increase in the levels of activation of MAPK is observed (Figure 1).…”

“…Although spontaneous activation of ErbB-2 might occur in cells that overexpress the receptor, transactivation by other receptors of the same family such as EGFR and ErbB-3 might lead to its phosphorylation [26]. Therefore, it is conceivable that this phenomenon might play a role in determining the sensitivity/resistance to anti-ErbB-2 agents.…”

“…More importantly, the levels of activation rather than the expression of the target receptors might result more informative for an appropriate selection of patients that might benefit of this approach. Indeed, no correlation between the levels of expression of EGFR and activity of anti-EGFR agents has been found in different tumor types, including lung and colon carcinoma [26]. Interestingly, increasing evidence suggests that the levels of expression of EGFR ligands correlates with activity of the anti-EGFR monoclonal antibody cetuximab in metastatic colorectal cancer patients [46].…”

Clinical significance of heparin-binding epidermal growth factor-like growth factor in peritoneal fluid of ovarian cancer

“…Impairment of the epidermal growth factor (EGF) system has been implicated in the pathogenesis of different types of carcinomas (Salomon et al, 1995;Normanno et al, 2003). As described in the literature (Salomon et al, 1995;Normanno et al, 2003), EGF receptor (EGFR) overexpression occurs in 35 -70% of all primary OVCAs and the overexpression of ErbB2 is correlated to clinical outcome.…”

Recombinant polyclonal antibodies for cancer therapy

“…In addition, Panorex (CO17-1A [Herlyn et al, 1979[Herlyn et al, , 1980), a murine MAb reactive with the tumor associated antigen Ep-CAM-was approved in Germany for the treatment of colorectal cancer [Riethmuller et al, 1994[Riethmuller et al, , 1998]. Although remissions have been noted using MAbs for cancer treatment, most were only temporary [Divgi and Larson, 1995;Riethmuller et al, 1998;Ben-Efraim, 1999;Macdonald, 1999;Normanno et al, 2003]. The emergence of tumor cell ''escape variants,'' which are no longer affected by the antibody, remains the major problem.…”