Decorin Suppresses Prostate Tumor Growth through Inhibition of Epidermal Growth Factor and Androgen Receptor Pathways

Epidermal growth factor receptor (EGFR) and androgen receptor (AR) pathways play pivotal roles in prostate cancer progression. Therefore, agents with dual-targeting ability may have important therapeutic potential. Decorin, a proteoglycan present in the tumor microenvironment, is known to regulate matrix assembly, growth factor binding, and receptor tyrosine kinase activity. Here, we show that in prostate-specific Pten^P-/- mice, a genetically defined, immune-competent mouse model of prostate cancer, systemic delivery of decorin inhibits tumor progression by targeting cell proliferation and survival pathways. Moreover, in human prostate cancer cells, we show that decorin specifically inhibits EGFR and AR phosphorylation and cross talk between these pathways. This prevents AR nuclear translocation and inhibits the production of prostate specific antigen. Further, the phosphatidylinositol-3 kinase (PI3K)/Akt cell survival pathway is suppressed leading to tumor cell apoptosis. Those findings highlight the effectiveness of decorin in the presence of a powerful genetic cancer risk and implicate decorin as a potential new agent for prostate cancer therapy by targeting EGFR/AR-PI3K-Akt pathways.     

Epidermal Growth Factor Receptor Inhibition in Lung Cancer: Status 2012

Lung cancer is the most common cause of cancer deaths. Most patients present with advanced-stage disease, and the prognosis is generally poor. However, with the understanding of lung cancer biology, and development of molecular targeted agents, there have been improvements in treatment outcomes for selected subsets of patients with non–small-cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated significantly improved tumor responses and progression-free survival in subsets of patients with advanced NSCLC, particularly those with tumors harboring activating EGFR mutations. Testing for EGFR mutations is a standard procedure for identification of patients who will benefit from first-line EGFR TKIs. For patients with advanced NSCLC and no activating EGFR mutations (EGFR wild-type) or no other driving oncogenes such as ALK-gene rearrangement, chemotherapy is still the standard of care. A new generation of EGFR TKIs, targeting multiple receptors and with irreversible bindings to the receptors, are in clinical trials and have shown encouraging effects. Research on primary and acquired resistant mechanisms to EGFR TKIs are ongoing. Monoclonal antibodies (e.g. cetuximab), in combination with chemotherapy, have demonstrated improved outcomes, particularly for subsets of NSCLC patients, but further validations are needed. Novel monoclonal antibodies are combined with chemotherapy, and randomized comparative studies are ongoing. This review summarizes the current status of EGFR inhibitors in NSCLC in 2012 and some of the major challenges we are facing.     

Inhibition of Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor Phosphorylation on Tumor-Associated Endothelial Cells Leads to Treatment of Orthotopic Human Colon Cancer in Nude Mice

The purpose of our study was to determine whether the dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) signaling pathways in tumor-associated endothelial cells can inhibit the progressive growth of human colon carcinoma in the cecum of nude mice. SW620CE2 human colon cancer cells growing in culture and orthotopically in the cecum of nude mice expressed a high level of transforming growth factor alpha (TGF-α) and vascular endothelial growth factor (VEGF) but were negative for EGFR, human epidermal growth factor receptor 2 (HER2), and VEGFR. Double immunofluorescence staining revealed that tumor-associated endothelial cells expressed EGFR, VEGFR2, phosphorylated EGFR (pEGFR), and phosphorylated VEGFR (pVEGFR). Treatment of mice with either 7H-pyrrolo [2,3-d]-pyrimidine lead scaffold (AEE788; an inhibitor of EGFR and VEGFR tyrosine kinase) or CPT-11 as single agents significantly inhibited the growth of cecal tumors (P < .01); this decrease was even more pronounced with AEE788 combined with CPT-11 (P < .001). AEE788 alone or combined with CPT-11 also inhibited the expression of pEGFR and pVEGFR on tumor-associated endothelial cells, significantly decreased vascularization and tumor cell proliferation, and increased the level of apoptosis in both tumor-associated endothelial cells and tumor cells. These data demonstrate that targeting EGFR and VEGFR signaling on tumor-associated endothelial cells provides a viable approach for the treatment of colon cancer.     

Targeting Epidermal Growth Factor Receptor by MiRNA-145 Inhibits Cell Growth and Sensitizes NSCLC Cells to Erlotinib

Background: Despite effective activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as erlotinib, all non-small cell lung cancer (NSCLC) patients eventually acquire resistance to these agents. Studies have demonstrated that down-regulation of miRNA-145 leads to enhancement of EGFR expression, cell proliferation and metastasis. The aim of this study was to investigate the effect of miRNA-145 on sensitivity of the A549 NSCLC cells to erlotinib. Methods: Quantitative real-time PCR was used to examine the effect of miRNA-145 on EGFR expression. The effect of miRNA-145 on cell growth and sensitivity the lung cancer cells to erlotinib was examined by trypan blue and MTT assays, respectively. The combination index was calculated using the non-constant method of Chou-Talalay. Apoptosis was determined by ELISA cell death assay. Results: We found that miRNA-145 was markedly suppressed the expression of EGFR and inhibited the cancer cell growth, relative to blank control and negative control miRNA (p<0.05). Pretreatment with miRNA-145 synergistically enhanced the sensitivity of the lung cancer cells to erlotinib. Results of apoptosis assay revealed that miRNA-145 can induce apoptosis and increase the erlotinib-mediated apoptosis. Conclusions: Our data demonstrate that miRNA-145 play a critical role in the lung cancer cell growth, survival and EGFR-TKIs resistance possibly by regulation of EGFR. Therefore, miRNA-145 replacement therapy can become a new therapeutic strategy in lung cancer.     

Epidermal Growth Factor-dependent Dissociation of CrkII Proto-oncogene Product from the Epidermal Growth Factor Receptor in Human Glioma Cells

Human glioma cells frequently overexpress epidermal growth factor receptor (EGFR). We found that the CrkII proto-oncogene product was associated with the EGFR in human glioma cells in the absence of epidermal growth factor (EGF). EGF stimulation of glioma cells induced the phosphorylation of tyrosine 221 of the CrkII protein, which correlates with its dissociation from the EGFR. By contrast, Shc and Grb2 were inducibly associated with the EGFR in response to EGF stimulation of glioma cells. In A431 cells, epidermoid carcinoma cells which overexpress EGFR, CrkII was tyrosine-phosphorylated and associated with the EGFR in an EGF-dependent manner. Therefore, the dissociation of CrkII from the EGFR upon stimulation with EGF appears to be specific to glioma cells. The Cbl oncogene product was also tyrosine-phosphorylated in U87MG glioma cells upon EGF stimulation. However, unlike in other cell lines, CrkII was not inducibly bound to Cbl in U87MG glioma cells. Thus, EGF-dependent binding of CrkII to phosphotyrosine-containing proteins appears to be suppressed in glioma cells. To evaluate the physiological role of dissociation of CrkII from EGFR, we expressed the CrkII-23 mutant in glioma cells. CrkII-23 mutant, which was isolated as a suppressor gene of the EGF-dependent transformation of NRK cells, binds constitutively to EGFR. We found that expression of CrkII-23 inhibited the anchorage-independent growth of the glioma cells in the presence of EGF. Taken together, these data implicate EGF-dependent dissociation of CrkII from EGFR in the oncogenicity of human glioma cells.     

表皮生长因子及其受体在大肠癌中的表达及其意义

目的通过检测表皮生长因子及其受体在大肠癌中的表达，探讨其在大肠癌中的意义。方法应用SP法免疫组化方法检测10例正常大肠黏膜、64例大肠癌组织中表皮生长因子及其受体的表达。结果正常大肠黏膜中表皮生长因子及其受体均为阴性表达，而其在大肠癌中的表达分别为51％和66％，与正常组比较有非常显著性差异（P〈0．01）；在大肠癌中表皮生长因子与其受体存在显著正相关性（P〈0．01）。结论表皮生长因子及其受体在大肠癌的发生发展过程中起着重要的作用。     

Immunohistochemical Study of Estradiol, Epidermal Growth Factor, Transforming Growth Factor Alpha and Epidermal Growth Factor Receptor in Endometrial Neoplasia

In a total of 113 cases of endometrial neoplasm, we studiedthe immunohistochemical expression of estradiol (E2), epidermalgrowth factor (EGF), transforming growth factor alpha (TGF),and epidermal growth factor receptor (EGFR). Positive immunoreactivityof E2 was found in 61% of the neoplasms. E2 immunoreactivitycorrelated well with high histologic grade and early clinicalstage. Positive immunoreactivity for ECF or ECFR was found in25.6% or 53.1% of the neoplasms, respectively. However, thiswas unrelated to histologic grade or clinical stage. On theother hand, TGF immunoreactivity was found in 67% of endometrialneoplasias and was correlated with poor histologic grade andadvanced stage. Contingency tables indicated a significant negativeassociation between the status of E2 and that of TGF. Simultaneousexpression of E2, EGF and EGFR, or E2, TGF and EGFR was foundin 6.8% and 15.9% of endometrial carcinomas, respectively. Theseresults suggest that a predominant number of endometrial carcinomasescape autocrine/paracrine growth regulation by EGF and E2 orTGF and E2, and that TGF may be involved in the progressionof endometrial carcinoma.     

Epidermal Growth Factor Receptor Antagonists in Pancreatic Cancer

Pancreatic cancer is the fourth leading cause of cancer-related death in North America and is associated with an extremely bleak prognosis. Advances in the treatment of this devastating disease will require novel approaches. A key therapeutic strategy is inhibition of the epidermal growth factor receptor (EGFR). The EGFR is overexpressed in pancreatic cancer and is associated with poor prognosis. This article summarizes current knowledge of the role of EGFR antagonists in pancreatic cancer and focuses on the preclinical background and EGFR inhibitors in clinical development including erlotinib, gefitinib, cetuximab, and matuzumab. Erlotinib in combination with chemotherapy and radiation has encouraging antitumor activity in locally advanced pancreatic cancer. A phase II trial of cetuximab and gemcitabine in advanced pancreatic cancer showed promising activity and 1-year survival. Proof of principle for EGFR inhibition in this disease was provided by a phase III trial in advanced pancreatic cancer that demonstrated a survival advantage with erlotinib in combination with gemcitabine compared with placebo plus gemcitabine. Current research efforts are aimed at determining predictive factors for response to EGFR inhibitors, defining the role of EGFR blockade in early stages of disease, and exploring combinations with other molecular-targeted approaches.     

Epidermal Growth Factor Receptor Inhibition in the Management of Squamous Cell Carcinoma of the Lung

Molecular therapies targeting epidermal growth factor receptor (EGFR) have had a profound impact on the management of advanced non-small cell lung cancer (NSCLC). EGFR inhibition with EGFR tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR monoclonal antibodies (mAbs) in squamous NSCLC (sqNSCLC) remains controversial in patients whose tumors are not known to harbor EGFR mutations. Recent meta-analyses of EGFR-inhibition randomized trials that are adequately powered for histological subgroup analysis and anti-EGFR trials limited to patients with squamous histology afford the opportunity to revisit EGFR treatment in sqNSCLC. In unselected patients with sqNSCLC who are not eligible for chemotherapy, EGFR-TKI therapy is a valid treatment option over placebo or best supportive care, with improved progression-free survival noted in randomized controlled trials in both the first- and second-line setting and improved overall survival (OS) in the second-line setting. In patients eligible for chemotherapy, first-line combination regimens with anti-EGFR mAbs have been shown to improve OS over chemotherapy alone in patients with squamous histology in meta-analysis and more recently in the SQUIRE sqNSCLC trial (chemotherapy with and without necitumumab). In sqNSCLC patients who respond to induction chemotherapy, maintenance therapy with erlotinib delays disease progression and may improve the survival of patients with stable disease. In the second-line setting, survival outcomes are comparable between chemotherapy and EGFR-TKIs in meta-analysis, with the latter being more tolerable as a second-line therapy. Newer-generation EGFR-TKI therapies may further benefit patients with sqNSCLC who have failed first-line chemotherapy, given the positive trial results from LUX-Lung 8 (afatinib vs. erlotinib). EGFR is a valid therapeutic target in unselected/EGFR wild-type patients with squamous cell carcinoma of the lung. With the recent approval of immune checkpoint inhibitors in the second-line management of advanced sqNSCLC and their adoption as a new standard of care, there exists an opportunity for novel combination therapies to increase therapeutic efficacy and durable tumor control. As more targeted agents are approved, combination regimens that include an anti-EGFR agent should be evaluated, and the optimal sequencing of targeted therapies should be defined.

Implications for Practice:

Anti-epidermal growth factor receptor (EGFR) therapies remain controversial in unselected/wild-type EGFR squamous non-small cell lung cancer (NSCLC). Recent meta-analyses and squamous-only NSCLC EGFR-inhibition trials have overcome the power limitations of early trials and can now inform the management of squamous NSCLC with anti-EGFR therapies. With the approval of immunotherapeutics in the second-line management of squamous NSCLC, there exists an opportunity for novel combination therapies to improve efficacy and durable tumor control. The optimal timing and sequencing of available second-line targeted therapies, however, have yet to be defined. This review analyzes randomized clinical trials of EGFR inhibition in NSCLC and meta-analyses of these trials, with a focus on patients with squamous histology.     

表皮生长因子抑制剂在进展期及转移性膀胱癌靶向治疗中的研究进展

现在传统的组织病理学评价如分级和分期在预测膀胱癌的生物学行为方面受到限制。很多肌肉浸润的膀胱癌患者行根治性的膀胱切除术后,却因远处的转移而死亡,因此现在很多研究已证明膀胱癌的分子水平的改变及生物学特点,并以此分类膀胱肿瘤。最近研究发现表皮生长因子受体（EGFR）信号转导通路在膀胱癌细胞的增殖、转移和血管形成等方面有重要作用,因此,针对EGFR信号转导通路的新型药物已陆续开发和应用。文章综述了EGFR的结构、功能及EGFR抑制剂在膀胱癌治疗中的临床前期应用价值。     

Targeting the Epidermal Growth Factor Receptor in High-Grade Astrocytomas

Opinion statement  High-grade astrocytomas, including glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), are the most common and aggressive primary malignant brain tumors in adults. Despite improvements in survival with the addition of temozolomide to radiation in the adjuvant setting, the prognosis of patients affected by these tumors remains relatively poor. One approach to improve outcomes in these patients is to target the epidermal growth factor receptor (EGFR). EGFR-targeted therapy is a rational approach since EGFR overexpression and mutant EGFRvIII expression occur in approximately 50% of patients with GBM. Unfortunately, monotherapy with anti-EGFR agents in malignant gliomas has not provided the dramatic results sometimes seen with other targeted therapies, such as imatinib in chronic myelogenous leukemia. Anti-EGFR agents currently being studied in malignant gliomas include the tyrosine kinase inhibitors (TKI), monoclonal antibodies (MAb), and anti-EGFR vaccines. Of all these agents, the tyrosine kinase inhibitors—which include erlotinib and gefitinib—have been the most extensively tested in clinical trials. Retrospective analyses have highlighted co-expression of EGFRvIII and wild-type PTEN (phosphatase and tensin homologue deleted in chromosome 10) as a significant predictor of EGFR TKI response in patients with GBM. As the EGFR signaling pathway is exceptionally complex, newer approaches targeting multiple points in the pathway are being developed to improve treatment efficacy.