The epidermal growth factor receptor as a target for cancer therapy.

Abstract

Epidermal growth factor (EGF) receptors are expressed at high levels in about one third of epithelial cancers, and autocrine activation of EGF receptors appears to be critical for the growth of many tumors. We hypothesized that blockade of the binding sites for EGF and transforming growth factor-α on EGF receptors with an antireceptor monoclonal antibody (mAb) might be an effective anti-cancer therapy. We produced murine mAb 225 against EGF receptors and demonstrated blockade of receptor function, as well as inhibition of cell growth in cultures and in nude mouse xenografts. mAb C225 is the human:murine chimeric version of mAb 225. Cell cycle inhibition occurred in G 1 phase, and was due to upregulation of p27 Kip1 , resulting in inhibition of cyclin E/cyclin dependent kinase-2 activity and hypophosphorylation of Rb. In addition, the amount and/or activities of a number of proapoptotic molecules were enhanced. The antitumor activity in vivo against xenografts was at least partly attributable to reduced vascularization, resulting from decreased vascular endothelial growth factor and basic fibroblast growth factor production by the tumor cells. Metastasis of xenografts was curtailed with mAB C225 treatment, accompanied by a decrease in tumor production of MMP-9. Further studies showed that mAbs 225 and C225 enhanced the cytotoxicity of chemotherapy against xenografts of a variety of human cancer cell lines. Well established xenografts resistant to either mAb or drug treatment alone were eradicated by the combination therapy. Drugs for which this has been demonstrated include doxorubicin, paclitaxel, cisplatin, and topotecan. Antibody treatment also potentiated the responsiveness of human tumor xenografts to radiation therapy. These findings led to clinical trials of human:murine chimeric mAb C225 in combination with chemotherapy or radiotherapy. Results from phase I and II trials involving more than 500 patients are quite promising, in particular in advanced head and neck cancer treated with C225 plus cisplatin or radiation, in advanced colon cancer treated with C225 plus CPT-11, and in advanced pancreatic cancer treated with C225 plus gemcitabine. Phase III trials are now underway.

Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies

“…This confirms previously reported observations of differential inhibition of EGFR and MAPK phosphorylation in glioma cell lines (Li et al, 2003) and shows the effectiveness of gefitinib against EGFR signaling in human keratinocytes. To compare the effect of gefitinib with an anti-EGFR antibody, NHEK were treated with cetuximab, an anti-EGFR humanized chimeric mouse monoclonal antibody, which competitively inhibits receptor binding of EGF and other EGFR ligands (Mendelsohn, 2001). Figure 2C demonstrates Unlike gefitinib and cetuximab, pertuzumab, which is a HER2-specific antibody that interferes with its heterodimerization with other receptor members, was unable to block EGF stimulated EGFR or MAPK phosphorylations in NHEK ( Figure 3A).…”

Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells

“…To date, it has been reported that host-derived growth factors and angiogenic factors could be important contributors to tumor progression at different stages. Especially, tumor cells have been shown to secrete various humoral factors (for example, VEGF, platelet-derived growth factor, endo thelial growth factor, transforming growth factor-a and interleukin-8) into the tumor microenvironment, [29][30][31][32] and tumor growth requires the formation of mesenchymal stroma to promote angiogenesis and metastasis to specific distant organs. 33 Although angiogenesis has been the focus of tumor progression, lymphangiogenesis also plays an important role in tumor progression and metastasis.…”

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs): Simple drugs with a complex mechanism of action?

“…In particular, in order to obviate the immune response against the murine antibodies, a chimeric human:murine version of the anti-EGFR 225 antibody has been generated (Goldstein et al, 1995). Phase III studies of the C225 antibody in combination with either chemotherapy or radiotherapy are ongoing in cancer patients (Mendelsohn, 2001).…”