Growth factor receptor inhibitor

About: Growth factor receptor inhibitor is a research topic. Over the lifetime, 4730 publications have been published within this topic receiving 297500 citations.

Cross talk between peptide growth factor and estrogen receptor signaling systems.

Abstract: Epidermal growth factor reproduces many of the effects of estrogen on the murine female reproductive tract and may partially mediate estrogen-induced growth and differentiation. The mechanism by which the actions of estrogens and epidermal growth factor (EGF) converge is unknown. The studies described herein were performed to investigate the possibility that some of the actions of EGF may be mediated through the estrogen receptor. A specific estrogen receptor (ER) antagonist inhibited estrogenlike effects of EGF in the mouse uterus, specifically induction of DNA synthesis and phosphatidylinositol turnover. In addition, EGF elicited enhanced nuclear localization of uterine ER and formation of a unique nuclear form of ER that is present after estrogen treatment. These in vivo observations indicated that EGF may elicit some of its actions by activation of nuclear ER. Thus, the effect of peptide growth factors on activation of a consensus estrogen response element was assessed in Ishikawa human endometrial adenocarcinoma cells, which contain negligible ER levels, and in BG-1 human ovarian adenocarcinoma cells, which contain abundant ER. EGF and TGF alpha induced transcriptional activation of a consensus estrogen response element (ERE) in an ER-dependent manner in both cell types. In addition, insulinlike growth factor I (IGF-I) was as potent as 17 beta-estradiol in BG-1 cells. Synergism between growth factors and estrogen was observed in both cell types, although synergism was not observed between the different classes of growth factors [i.e., transforming growth factor alpha (TGF alpha) and IGF-I] in BG-1 cells. The most potent activator of ERE-dependent transcription was a protein kinase C activator (TPA), which acted synergistically with 17 beta-estradiol. A protein kinase C inhibitor abolished the effect of TPA but not that of 17 beta-estradiol, IGF-I, or TGF alpha. A protein kinase A activator elicited ER-dependent activation of transcription and did not synergize with estrogen or growth factors. In conclusion, some physiologic actions of peptide growth factors are dependent on ER. Indeed, growth factors are capable of eliciting ER-dependent activation of an ERE. Both the protein kinase A and protein kinase C pathways can elicit ER-dependent transcriptional activation; however, it is unlikely that these pathways mediate the effects of peptide growth factors on the ER in BG-1 cells.

A stable IgG-like bispecific antibody targeting the epidermal growth factor receptor and the type I insulin-like growth factor receptor demonstrates superior anti-tumor activity

Abstract: The epidermal growth factor receptor (EGFR) and the type I insulin-like growth factor receptor (IGF-1R) are two cell surface receptor tyrosine kinases known to cooperate to promote tumor progression and drug resistance. Combined blockade of EGFR and IGF-1R has shown improved anti-tumor activity in preclinical models. Here, we report the characterization of a stable IgG-like bispecific antibody (BsAb) dual-targeting EGFR and IGF-1R that was developed for cancer therapy. The BsAb molecule (EI-04), constructed with a stability-engineered single chain variable fragment (scFv) against IGF-1R attached to the carboxyl-terminus of an IgG against EGFR, displays favorable biophysical properties for biopharmaceutical development. Biochemically, EI-04 bound to human EGFR and IGF-1R with sub nanomolar affinity, co-engaged the two receptors simultaneously, and blocked the binding of their respective ligands with similar potency compared to the parental monoclonal antibodies (mAbs). In tumor cells, EI-04 effectively inhibited EGFR and IGF-1R phosphorylation, and concurrently blocked downstream AKT and ERK activation, resulting in greater inhibition of tumor cell growth and cell cycle progression than the single mAbs. EI-04, likely due to its tetravalent bispecific format, exhibited high avidity binding to BxPC3 tumor cells co-expressing EGFR and IGF-1R, and consequently improved potency at inhibiting IGF-driven cell growth over the mAb combination. Importantly, EI-04 demonstrated enhanced in vivo anti-tumor efficacy over the parental mAbs in two xenograft models, and even over the mAb combination in the BxPC3 model. Our data support the clinical investigation of EI-04 as a superior cancer therapeutic in treating EGFR and IGF-1R pathway responsive tumors.

Isolation of the human placenta receptor for epidermal growth factor-urogastrone.

Abstract: EPIDERMAL growth factor-urogastrone (EGF-URO), a singlechain polypeptide of molecular weight ∼6,000, found both in the mouse1–3 and in man4–7, is both a potent stimulant of cell proliferation and an inhibitor of gastric acid secretion. Specific membrane receptors for EGF-URO can be detected in various tissues including human placenta8–11. Although the mouse and human polypeptide sequences differ at 16 positions, they can share the same receptor site in human tissues3,12. There has been considerable recent interest in EGF-URO and its receptor, not only because of the potent mitogenic and acid-inhibitory actions of the polypeptide, but also because of the association of viral13, chemical14 and spontaneous15 cell transformation with a specific reduction in cell receptors for EGF-URO. It is also believed that EGF-URO and its receptor may be involved in the development, maintenance, and differentiation of tissues as diverse as the lens16, the palate17 and the keratin layer of skin18. In experiments aimed at the isolation of the membrane receptor for EGF-URO, we have observed that, unlike the receptor for insulin19, but like the muscarinic receptor for acetylcholine20, the EGF-URO receptor loses its ligand recognition property following solubilisation with detergents. We therefore developed an affinity-labelling technique using glutaraldehyde, that can covalently crosslink the receptor with 125I-labelled EGF-URO before solubilisation21. Independently, Das and coworkers have developed a photoaffinity-labelling technique that can also be used to radiolabel the EGF-URO receptor before solubilisation22. Here we report the success of both our previously described glutaraldehyde crosslinking technique21 (using 125I-EGF-URO for receptor labelling) and of a newly developed photoaffinity-labelling technique (using a photolabile 125I-EGF-URO crosslinking reagent) to identify the EGF-URO receptor in human placenta membranes and to effect the isolation of the affinity-labelled receptor by affinity chromatography using lectin and murine EGF-URO antibody–Agarose columns.