Development Of Epidermal Growth Factor Receptor Research Articles

Dual targeting pH responsive chitosan nanoparticles for enhanced active cellular internalization of gemcitabine in non-small cell lung cancer

Lung cancer (LC), related with the enhanced expression of epidermal growth factor receptor (EGFR) and sialic acid binding receptors (glycan) brought about the development of EGFR and glycan receptor specific anticancer therapeutics. The current study assessed the formulation, physiochemical characterization, in vitro and in vivo effects of sialic acid (SA) and cetuximab (Cxmab) decorated chitosan nanoparticles (CSN-NPs) loaded with gemcitabine (GMC) targeted to glycan and EGFR over-expressing non-small-cell lung-cancer (NSCLC) A-549 cells. Chitosan (CSN) was conjugated with sialic acid via EDC/NHS chemistry followed by gemcitabine loaded sialic acid conjugated chitosan nanoparticles (GMC-CSN-SA-NPs) were prepared by ionic gelation method decorated with Cxmab by electrostatic interaction. In vitro cytotoxicity of NPs quantified using cell based MTT, DAPI and Annexing-V/PI apoptosis assays showed superior antiproliferative activity of targeted nanoformulations (GMC-CSN-SA-Cxmab-NPs ≫ GMC-CSN-SA-NPs, GMC-CSN-Cxmab-NPs) over non-targeted nanoformulation (GMC-CSN-NPs) against A-549 cells. In vivopharmacokinetic study showed superior bioavailability and in vivo therapeutic efficacy investigation exhibited strongest anticancer activity of glycan and EGFR targeted NPs (GMC-CSN-SA-Cxmab-NPs). GMC-CSN-SA-Cxmab-NPs demonstrated enhanced cellular internalization and better therapeutic potential, by specifically targeting glycan and EGFR on NSCLC A-549 cells and B[a]P induced lung cancer mice model, hence it might be a good substitute for non-targeted, conventional chemotherapy.

Abstract 968: β-catenin plays an important role in lung tumor development induced by EGFR mutations

Abstract The discovery of somatic mutations in epidermal growth factor receptor (EGFR) and the development of EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have revolutionized treatment for non-small cell lung cancer (NSCLC). Resistance to TKIs emerges in almost all patients, but currently no effective treatment is available.Therefore, novel strategies to either prevent or overcome resistance are sorely needed. Here we show that β-catenin is essential for development of EGFR mutated lung cancers. We found that β-catenin was upregulated, translocated to the nucleus, and subsequently activated in both EGFR mutated lung cancer cell lines and EGFR mutation driven lung tumors. We demonstrated that mutant EGFR preferentially bound to β-catenin and caused tyrosine-phosphorylation of β-catenin. Tyrosine-phosphorylation of β-catenin led to stabilization, nuclear translocation, and transcriptional activity particularly in cells harboring EGFR-L858R (LR)-T790M (TM). Pharmacological β-catenin inhibition using ICG-001, which specifically blocks the CBP-β-catenin interaction, suppressed growth of both H1975 cells harboring EGFR-LR-TM and lung tumors in EGFR-LR-TM transgenic mice. To further examine whether β-catenin plays an important role in lung tumorigenesis, we generated an EGFR-LR-TM lung cancer mouse model in which the β-catenin gene (Ctnnb1) can be conditionally deleted. Genetic deletion of Ctnnb1 dramatically reduced lung tumor formation and showed significantly longer survival. Taken together, our data suggest that β-catenin plays an important role in mutant EGFR-driven lung tumorigenesis and that targeting the β-catenin pathway may provide novel strategies to prevent lung cancer development and/or overcome resistance to EGFR TKIs. Citation Format: Sohei Nakayama, Natasha J. Sng, Julian Carretero, Robert Welner, Yuichiro Hayashi, Mihoko Yamamoto, Tan J. Alistair, Norihiro Yamaguchi, Hiroyuki Yasuda, Li Danan, Kenzo Soejima, Soo A. Ross, Costa B. Daniel, Kwok-Kin Wong, Susumu S. Kobayashi. β-catenin plays an important role in lung tumor development induced by EGFR mutations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 968. doi:10.1158/1538-7445.AM2014-968

Growth factor receptors as targets for novel treatment strategies of neuroendocrine tumors

Both the epidermal growth factor receptor (EGFR) and the insulin-like growth factor receptor (IGFR) are commonly (over-)expressed in many cancers including neuroendocrine tumors (NETs); clinical trials indicate that these antigens have important roles in cancer etiology and progression. EGFR and IGFR thus provide rational targets for cancer therapies and a number of strategies influencing these receptors, and its downstream signal cascades, including monoclonal antibodies, tyrosine-kinase inhibitors or antisense oligonucleotides have been evaluated. In particular, monoclonal antibodies targeting the receptors' extracellular domains and small molecules blocking (tyrosine-) kinase activation intracellularly have already shown activity in clinical phase II trials of neuroendocrine tumors. The clinically well established somatostatin analogues are known to inhibit both insulin-like growth factor (IGF1) and vascular endothelial growth factor (VEGF) production in NETs. As generally neuroendocrine tumors and their metastases represent hypervascularized neoplasms, inhibition of VEGF or VEGF receptor (VEGFR)-tyrosine kinases (VEGFR-TK) is a rational approach to go for. Phase II studies have indeed provided evidence for the antineoplastic potency of VEGF or VEGFR-TK inhibition by either monoclonal antibodies, tyrosine kinase blockers or thalidomide in NETs. Some small molecules not only inhibit VEGFR but also EGFR or platelet derived growth factor receptor (PDGFR)-tyrosine kinases or c-KIT; several of these molecules have successfully been tested for their antiproliferative effects in NETs. The serine-threonine kinase mTOR is linked to several growth factor receptors including EGFR and IGFR. mTOR plays an important role in cell growth and cancer proliferation. Recently, everolimus, a macrolide mTOR inhibitor, has been combined with the somatostatin analogue octreotide for effective growth control of NET disease in a phase II study. However, many questions remain unanswered and future issues in the development of EGFR, IGF(R) or VEGF(R) inhibitors will include the identification of biological predictors of response, combination with other therapies and also their use in earlier stages of NET disease. In ongoing clinical trials EGFR and/or VEGF/VEGFR blockade or mTOR inhibitors are combined with either cytostatics or stable somatostatin analogues. In summary, growth factor receptors and their downstream signal cascades are very promising targets for novel treatment strategies of NETs.

Anti-epidermal growth factor receptor strategies to enhance radiation action.

The epidermal growth factor receptor (EGFR) has emerged as a central molecular target for modulation in cancer therapeutics, since EGFR signaling affects many factors that in turn promote tumor growth, progression and metastasis. In addition, radiobiological investigations have also defined a critical role for EGFR in mediating cytoprotective and pro-proliferative responses in human cancer cells after ionizing radiation, that contribute at least in part to accelerated tumor cell repopulation. This led to the additional development of EGFR as a target to enhance radiation efficacy. Several anti-EGFR strategies have been put forth demonstrating a favorable biological interaction between EGFR blockade and radiation. However, further preclinical investigations are necessary to better explore mechanisms of action and efficacy of combined treatment modalities. Although some of the anti-EGFR approaches have already reached clinical testing in combination with radiation, it is still too early to establish a clinical proof for the ultimate role of EGFR inhibition in combination with radiation. This article focuses primarily on anti-EGFR approaches to modulate radiation response.