Showing papers on "Growth factor receptor inhibitor published in 2010"

Rational, biologically based treatment of EGFR -mutant non-small-cell lung cancer

Abstract: Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) was first recognized in 2004 as a distinct, clinically relevant molecular subset of lung cancer. The disease has been the subject of intensive research at both the basic scientific and clinical levels, becoming a paradigm for how to understand and treat oncogene-driven carcinomas. Although patients with EGFR-mutant tumours have increased sensitivity to tyrosine kinase inhibitors (TKIs), primary and acquired resistance to these agents remains a major clinical problem. This Review summarizes recent developments aimed at treating and ultimately curing the disease.

Angiogenesis inhibitors: current strategies and future prospects.

Abstract: Angiogenesis has become an attractive target for drug therapy because of its key role in tumor growth. An extensive array of compounds is currently in preclinical development, with many now entering the clinic and/or achieving approval from the US Food and Drug Administration. Several regulatory and signaling molecules governing angiogenesis are of interest, including growth factors (eg, vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, and epidermal growth factor), receptor tyrosine kinases, and transcription factors such as hypoxia inducible factor, as well as molecules involved in mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling. Pharmacologic agents have been identified that target these pathways, yet for some agents (notably thalidomide), an understanding of the specific mechanisms of antitumor action has proved elusive. The following review describes key molecular mechanisms and novel therapies that are on the horizon for antiangiogenic tumor therapy.

Epidermal growth factor receptor (EGFR) in lung cancer: an overview and update

Abstract: Epidermal growth factor receptor is a trans-membrane glycoprotein with an extracellular epidermal growth factor binding domain and an intracellular tyrosine kinase domain that regulates signaling pathways to control cellular proliferation. Epidermal growth factor receptor binding to its ligand results in autophosphorylation by intrinsic tyrosine/kinase activity, triggering several signal transduction cascades. Constitutive or sustained activation of these sequences of downstream targets is thought to yield more aggressive tumor phenotypes. Mutations in epidermal growth factor receptor have been discovered in association with some lung cancers. Lung adenocarcinomas with mutated epidermal growth factor receptor have significant responses to tyrosine kinase inhibitors, although for unselected patients it does not appear to have a survival benefit. However, in a subset of patients (non-smoking Asian women with adenocarcinoma, particularly with a bronchioloalveolar carcinoma), there appears to be a significant survival advantage. Both EGFR mutation and gene amplification status may be important in determining which tumors will respond to tyrosine kinase inhibitors.

CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor receptor, and human epidermal growth factor receptor 2, exerts potent anticancer activity.

Abstract: Receptor tyrosine kinase inhibitors have recently become important therapeutics for a variety of cancers. However, due to the heterogeneous and dynamic nature of tumors, the effectiveness of these agents is often hindered by poor response rates and acquired drug resistance. To overcome these limitations, we created a novel small molecule, CUDC-101, which simultaneously inhibits histone deacetylase and the receptor kinases epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in cancer cells. Because of its integrated histone deacetylase inhibition, CUDC-101 synergistically blocked key regulators of EGFR/HER2 signaling pathways, also attenuating multiple compensatory pathways, such as AKT, HER3, and MET, which enable cancer cells to escape the effects of conventional EGFR/HER2 inhibitors. CUDC-101 displayed potent antiproliferative and proapoptotic activities against cultured and implanted tumor cells that are sensitive or resistant to several approved single-targeted drugs. Our results show that CUDC-101 has the potential to dramatically improve the treatment of heterogeneous and drug-resistant tumors that cannot be controlled with single-target agents. Further, they provide a framework to create individual small molecules that simultaneously antagonize multiple biochemically distinct oncogenic targets, suggesting a general paradigm to surpass conventional, single-target cancer therapeutics. Cancer Res; 70(9); 3647-56. (c)2010 AACR.

Emerging Targeted Therapies for Breast Cancer

Abstract: Increased understanding of the molecular events involved in cancer development has led to the identification of a large number of novel targets and, in parallel, to the development of multiple approaches to anticancer therapy. Targeted therapy focuses on specific molecules in the malignant cell signal transduction machinery, including crucial molecules involved in cell invasion, metastasis, apoptosis, cell-cycle control, and tumor-related angiogenesis. In breast cancer, two new targeted agents have recently been approved: lapatinib, directed against the human epidermal growth factor receptor 2 (HER2); and bevacizumab, directed against vascular endothelial growth factor (VEGF). Multiple other targeted agents are under evaluation in clinical trials, including inhibitors of the epidermal growth factor receptor (EGFR), dual EGFR and HER2 inhibitors, other VEGF or VEGF-receptor inhibitors, and agents that alter crucial signaling pathways, such as RAS/MEK/ERK; phosphatidylinositol-3-kinase/Akt/ mammalian target of rapamycin; insulin-like growth factor/insulin-like growth factor receptor; poly (ADPribose) polymerase 1; and others. In this review, we present the most promising studies of these new targeted therapies and novel combinations of targeted therapies with traditional cytotoxic agents. J Clin Oncol 28:3366-3379. © 2010 by American Society of Clinical Oncology

Management of breast cancer with targeted agents: importance of heterogenicity

Abstract: Breast cancer is a heterogeneous disease with different molecular drivers regulating its growth, survival and treatment response. Drug development efforts have resulted in agents against new molecular targets that are active against only those tumors with the targeted molecular alteration or phenotype. The authors critically discuss the recently established and investigational strategies for the treatment of the main breast cancer subtypes. Breast cancer is a heterogeneous disease with different molecular drivers regulating its growth, survival and response to therapy. Breast cancer is divided in three major subtypes based on the pattern of expression of hormone receptors and HER2: luminal tumors (or HR positive), HER2 amplified tumors, and the remaining subtypes being collectively referred to as triple-negative breast cancer. While tumors within these subtypes have similar gene-expression patterns, clinical outcomes, and response to therapy, this division is far from perfect and subgroups within these groups are beginning to be identified. In terms of therapy, an increasingly rational drug development effort has resulted in agents against new molecular targets that are active against only those tumors with the targeted molecular alteration or phenotype. These agents include receptor and non-receptor tyrosine kinase inhibitors (HER1, HER2, HER3, insulin-like growth factor receptor, c-met, fibroblast growth factor receptor and HSP 90 inhibitors), intracellular signaling pathways (PI3K, AKT, mTOR), angiogenesis inhibitors and agents that interfere with DNA repair (PARP inhibitors). Thus, the overall management of breast cancer will increasingly require an understanding of breast cancer heterogeneicity, the biological nature of any given tumor as well the existence of increased personalized treatment options.

ALK1-Fc Inhibits Multiple Mediators of Angiogenesis and Suppresses Tumor Growth

Abstract: Activin receptor–like kinase-1 (ALK1) is a type I, endothelial cell–specific member of the transforming growth factor-β superfamily of receptors known to play an essential role in modulating angiogenesis and vessel maintenance. In the present study, we sought to examine the angiogenic and tumorigenic effects mediated upon the inhibition of ALK1 signaling using a soluble chimeric protein (ALK1-Fc). Of 29 transforming growth factor-β–related ligands screened by surface plasmon resonance, only bone morphogenetic protein (BMP9) and BMP10 displayed high-affinity binding to ALK1-Fc. In cell-based assays, ALK1-Fc inhibited BMP9-mediated Id-1 expression in human umbilical vein endothelial cells and inhibited cord formation by these cells on a Matrigel substrate. In a chick chorioallantoic membrane assay, ALK1-Fc reduced vascular endothelial growth factor–, fibroblast growth factor–, and BMP10-mediated vessel formation. The growth of B16 melanoma explants was also inhibited significantly by ALK1-Fc in this assay. Finally, ALK1-Fc treatment reduced tumor burden in mice receiving orthotopic grafts of MCF7 mammary adenocarcinoma cells. These data show the efficacy of chimeric ALK1-Fc proteins in mitigating vessel formation and support the view that ALK1-Fc is a powerful antiangiogenic agent capable of blocking vascularization. Mol Cancer Ther; 9(2); 379–88. ©2010 AACR.

Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

Abstract: The hedgehog (Hh)/glioma-associated oncogene (GLI) signaling network is among the most important and fascinating signal transduction systems that provide critical functions in the regulation of many developmental and physiological processes. The coordinated spatiotemporal interplay of the Hh ligands and other growth factors is necessary for the stringent control of the behavior of diverse types of tissue-resident stem/progenitor cells and their progenies. The activation of the Hh cascade might promote the tissue regeneration and repair after severe injury in numerous organs, insulin production in pancreatic β-cells, and neovascularization. Consequently, the stimulation of the Hh pathway constitutes a potential therapeutic strategy to treat diverse human disorders, including severe tissue injuries; diabetes mellitus; and brain, skin, and cardiovascular disorders. In counterbalance, a deregulation of the Hh signaling network might lead to major tissular disorders and the development of a wide variety of aggressive and metastatic cancers. The target gene products induced through the persistent Hh activation can contribute to the self-renewal, survival, migration, and metastasis of cancer stem/progenitor cells and their progenies. Moreover, the pivotal role mediated through the Hh/GLI cascade during cancer progression also implicates the cooperation with other oncogenic products, such as mutated K-RAS and complex cross-talk with different growth factor pathways, including tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), Wnt/β-catenin, and transforming growth factor-β (TGF-β)/TGF-β receptors. Therefore, the molecular targeting of distinct deregulated gene products, including Hh and EGFR signaling components and other signaling elements that are frequently deregulated in highly tumorigenic cancer-initiating cells and their progenies, might constitute a potential therapeutic strategy to eradicate the total cancer cell mass. Of clinical interest is that these multitargeted approaches offer great promise as adjuvant treatments for improving the current antihormonal therapies, radiotherapies, and/or chemotherapies against locally advanced and metastatic cancers, thereby preventing disease relapse and the death of patients with cancer.

Human oocyte maturation is dependent on LH-stimulated accumulation of the epidermal growth factor-like growth factor, amphiregulin

Abstract: BACKGROUND The LH surge promotes ovulation via activation of multiple signaling networks in the ovarian follicle. Studies in animal models have shown the importance of LH-induced activation of the epidermal growth factor (EGF)signaling network in critical peri-ovulatory events. We investigated the biological significance of regulatory mechanisms mediated by EGF-like growth factors during LH stimulation in humans.

Growth factor interactions in bone regeneration

Abstract: Bone regeneration is a complex process regulated by a large number of bioactive molecules. Many growth factors and cytokines involved in the natural process of bone healing have been identified and tested as potential therapeutic candidates to enhance the regeneration process. Although many of these studies show an enhancement of the bone regeneration process by a single drug therapy, in vivo bone regeneration is the result of a complex interplay between the applied growth factor and various endogenous produced growth factors. To investigate these growth factor interactions, various studies have investigated the effect of growth factor combinations on bone regeneration. This review provides an overview of the growth factor and cytokine combinations tested in translational bone regeneration studies and shows that their interaction may result in an enhancement or inhibition of bone formation.

Peptide-based interference of the transmembrane domain of neuropilin-1 inhibits glioma growth in vivo

Abstract: Angiogenesis in glioblastoma is largely dependent on vascular endothelial growth factor (VEGF) signalling. Consistently, the VEGF coreceptor NRP1 promotes angiogenesis and tumour growth in gliomas. Here, we provide data showing that an innovative peptidic tool targeting the transmembrane domain of NRP1 efficiently blocks rat and human glioma growth in vivo. We show both in vivo and in vitro that the antitumour effect results from the anti-proliferative, anti-migratory and anti-angiogenic properties of the compound. The proposed NRP1 antagonizing peptide is therefore a promising novel class of anti-angiogenic drugs that might prolong glioma patient survival. Our results finally show for the first time that the transmembrane domain of important signalling receptors can be antagonized in vivo thereby providing a new avenue towards the development of atypical antagonists with strong therapeutic potential.

Clinicopathological significance of platelet-derived growth factor (PDGF)-B and vascular endothelial growth factor-A expression, PDGF receptor-β phosphorylation, and microvessel density in gastric cancer

Abstract: Background Angiogenesis is important in the growth and metastasis of various kinds of solid tumors, including gastric cancers. The angiogenic process is triggered by several key growth factors, including vascular endothelial growth factor (VEGF)-A and platelet-derived growth factor (PDGF)-B, that are secreted by tumors. Our aim was to define: i) the expression pattern of VEGF-A and PDGF-B in tumor cells and the activation of PDGF receptor (PDGFR)-β tyrosine kinase in stromal cells of human gastric adenocarcinomas; and ii) the relationship between VEGF-A and PDGF-B expression and microvessel density (MVD), to determine if there is a rationale for a new therapeutic strategy.

Vascular endothelial growth factor receptor-1 in human cancer: concise review and rationale for development of IMC-18F1 (Human antibody targeting vascular endothelial growth factor receptor-1).

Abstract: The human vascular endothelial growth factor receptor-1 (VEGFR-1, or Flt-1) is widely expressed in normal and pathologic tissue and contributes to the pathogenesis of both neoplastic and inflammatory diseases. In human cancer, VEGFR-1 mediated signaling is responsible for both direct tumor activation and angiogenesis. VEGFR-1 mediated activation of nonmalignant supporting cells, particularly stromal, dendritic, hematopoietic cells, and macrophages, is also likely important for cancer pathogenesis. VEGFR-1 is also hypothesized to enable the development of cancer metastases by means of activation and premetastatic localization in distant organs of bone marrow-derived hematopoietic progenitor cells, which express VEGFR-1. IMC-18F1 is a fully human IgG1 antibody that binds to VEGFR-1 and has been associated with the inhibition of cancer growth in multiple in vitro and human tumor xenograft models. The preliminary results of phase 1 investigations have also indicated a favorable safety profile for IMC-18F1 at doses that confer antibody concentrations that are associated with relevant antitumor activity in preclinical models. Cancer 2010;116(4 suppl):1027–32. © 2010 American Cancer Society.

The upgraded role of HER3 and HER4 receptors in breast cancer.

Abstract: The human epidermal growth factor receptor (HER) family comprises four homologous members. The activation of these receptors affects essential tumorigenic processes and plays a crucial role in the pathogenesis of breast cancer. Among HER family members, EGFR and HER2 are the most studied. However, accumulating data provide evidence for the significance of HER3 and HER4 alterations in breast carcinogenesis. The combination of HER2 and HER3 receptors may be critical in breast cancer growth and progression. Moreover, HER3 may provide a route for resistance to agents targeting EGFR or HER2. Although a number of studies have demonstrated that HER3 overexpression is associated with poor prognosis in patients with breast cancer, other studies have indicated that HER3 overexpression may be a positive prognostic factor. With respect to HER4 receptor, the existing evidence suggests that HER4 signalling promotes differentiation and growth inhibition of breast cancer cells. In addition, HER4 is more consistently related with a favourable prognosis in breast cancer. HER4 has multiple different activities in the breast, and many of these functions are mediated by a soluble HER4 intracellular domain. In addition, loss of HER4 expression may represent a marker for resistance to tamoxifen. Because of the functional interdependency among the HER receptors, it is possible that the effect on cell proliferation and tumor growth depends on receptor trans-signalling. Therefore, clarifying how and the extent to which these different signalling pathways interact in breast carcinogenesis, may lead to additional therapeutic opportunities. This review presents an update on the role of HER3 and HER4 receptors in breast cancer. Moreover, we provide current data relating to the prognostic significance of these receptors, as well as their impact on the activity of HER-targeting therapies in patients with breast cancer.

Advances in Target Therapy for Lung Cancer

Abstract: Recent progress in molecular biology has shown that cancer cells acquire common phenotypes such as self-sufficiency of growth signals, resistance to anti-proliferative and apoptotic signals through the accumulation of genetic and epigenetic changes. Recently developed anticancer drugs target these molecular mechanisms and good results have been reported for various cancer types. In lung cancer, tyrosine kinase inhibitors specific for the epidermal growth factor receptor such as gefitinib and erlotinib have changed clinical practice dramatically. About half of the Japanese patients with lung cancers harbor an activating mutation of the epidermal growth factor receptor gene and they are very sensitive to epidermal growth factor receptor tyrosine kinase inhibitors. Progression-free survival of such patients is approximately 10 months when treated with gefitinib, whereas the survival for those treated with platinum doublet therapy is approximately 6 months. Target therapies against echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion protein or a mutated ERBB2 (v-ERB-B avian erythroblastic leukemia viral oncogene homologue 2) present in approximately 5% and approximately 3% of the Japanese patients with adenocarcinomas, respectively, are currently under development. Addition of an anti-epidermal growth factor receptor antibody, cetuximab, or anti-vascular endothelial growth factor antibody, bevacizumab, to platinum doublet therapy significantly but modestly prolonged the survival in recent clinical trials. However, clinical development of small molecule multi-kinase inhibitors including those targeting vascular endothelial growth factor receptors, such as vandetanib, sunitinib and sorafenib, has not been very successful. Through these collaborations among clinicians, basic researchers and pharmaceutical companies, it should be possible to individualize lung cancer treatment to turn this fatal disease into a chronic disorder and, eventually, to cure it.

Angiogenic Growth Factors and their Inhibitors in Diabetic Retinopathy

Abstract: Diabetic retinopathy is considered one of the vision-threatening diseases among working-age population. The pathogenesis of the disease is regarded multifactorial and complex: capillary basement membrane thickening, loss of pericytes, microaneuryms, loss of endothelial cells, blood retinal barrier breakdown and other anatomic lesions might contribute to macular edema and/or neovascularization the two major and sight threatening complications of diabetic retinopathy. A number of proangiogenic, angiogenic and antiangiogenic factors are involved in the pathogenesis and progression of diabetic retinal disease, Vascular Endothelial Growth Factor (VEGF) being one of the most important. Other growth factors, which are known to participate in the pathogenesis of the disease, are: Platelet Derived Growth Factor (PDGF), Fibroblast Growth Factor (FGF), Hepatocyte Growth Factor (HGF), Transforming Growth Factor (TGF), Placental Endothelial Cell Growth Factor (PlGF), Connective Tissue Growth Factor (CTGF). Other molecules that are involved in the disease mechanisms are: intergrins, angiopoietins, protein kinase C (PKC), ephrins, interleukins, leptin, angiotensin, monocyte chemotactic protein (MCP), vascular cell adhesion molecule (VCAM), tissue plasminogen activator (TPA), and extracellular matrix metalloproteinases (ECM-MMPs). However, the intraocular concentration of angiogenic factors is counterbalanced by the ocular synthesis of several antioangiogenic factors such as pigment epithelial derived factor (PEDF), angiostatin, endostatin, thrombospondin, steroids, atrial natriuretic peptide (ANP), inteferon, aptamer, monoclonal antibodies, VEGF receptor blocker, VEGF gene suppressors, intracellular signal transduction inhibitors, and extracellular matrix antagonists. Growth stimulation or inhibition by these factors depends on the state of development and differentiation of the target tissue. The mechanisms of angiogenesis factor action are very different and most factors are multipotential; they stimulate proliferation or differentiation of endothelial cells. This review attempts to briefly outline the knowledge about peptide growth factor involvement in diabetic retinopathy. Further ongoing research may provide better understanding of molecular mechanisms, disease pathogenesis and therapeutic interactions.

ZD6474, a dual tyrosine kinase inhibitor of EGFR and VEGFR-2, inhibits MAPK/ERK and AKT/PI3-K and induces apoptosis in breast cancer cells.

Abstract: Abnormalities in gene expression and signaling pathways downstream of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) contribute to the progression, invasion, and maintenance of the malignant phenotype in human cancers, including breast. Consequently, the dual kinase inhibitor of EGFR and VEGFR ZD6474 represents a promising biologically-based treatment that is currently undergoing clinical trials for non-small cell lung cancer. Patients suffering from breast cancers have a poor prognosis because of the lack of effective agents and treatment strategies. We hypothesized that inhibition of phosphorylation of the EGFR and VEGFR by ZD6474 would inhibit breast cancer cell proliferation and induce apoptosis. This hypothesis was tested using human breast cancer cell lines. ZD6474 inhibited cell proliferation in a dose-dependent manner, by blocking cell progression at the G(0)-G(1) stage, through downregulation of expression of cyclin D1 and cyclin E. In vitro, ZD6474 inhibited growth factor-induced phosphorylation of EGFR, VEGFR-2, MAPK and Akt. ZD6474 also downregulated anti-apoptotic markers including Bcl-2, upregulated pro-apoptotic signaling events involving expression of bax, activation of caspase-3, and induction of poly (ADP-ribose) polymerase during apoptosis. ZD6474 inhibited anchorage independent colony formation using soft agar assays, and invasion of breast cancer cells in vitro using Boyden chamber assays. In a xenograft model using human MDA-MB-231 breast cancer cells, ZD6474 inhibited tumor growth and induced cancer-specific apoptosis. Collectively, these data imply that ZD6474 a dual kinase inhibitor has potential for the targeted therapy of breast cancer.

Chemotherapy-Induced Activation of ADAM-17: A Novel Mechanism of Drug Resistance in Colorectal Cancer

Abstract: Purpose: We have shown previously that exposure to anticancer drugs can trigger the activation of human epidermal receptor survival pathways in colorectal cancer (CRC). In this study, we examined the role of ADAMs (a disintegrin and metalloproteinases) and soluble growth factors in this acute drug resistance mechanism. Experimental Design: In vitro and in vivo models of CRC were assessed. ADAM-17 activity was measured using a fluorometric assay. Ligand shedding was assessed by ELISA or Western blotting. Apoptosis was assessed by flow cytometry and Western blotting. Results: Chemotherapy (5-fluorouracil) treatment resulted in acute increases in transforming growth factor-α, amphiregulin, and heregulin ligand shedding in vitro and in vivo that correlated with significantly increased ADAM-17 activity. Small interfering RNA–mediated silencing and pharmacologic inhibition confirmed that ADAM-17 was the principal ADAM involved in this prosurvival response. Furthermore, overexpression of ADAM-17 significantly decreased the effect of chemotherapy on tumor growth and apoptosis. Mechanistically, we found that ADAM-17 not only regulated phosphorylation of human epidermal receptors but also increased the activity of a number of other growth factor receptors, such as insulin-like growth factor-I receptor and vascular endothelial growth factor receptor. Conclusions: Chemotherapy acutely activates ADAM-17, which results in growth factor shedding, growth factor receptor activation, and drug resistance in CRC tumors. Thus, pharmacologic inhibition of ADAM-17 in conjunction with chemotherapy may have therapeutic potential for the treatment of CRC. Clin Cancer Res; 16(13); 3378–89. ©2010 AACR.

Fibroblast growth factor receptor 3-IIIc mediates colorectal cancer growth and migration

Abstract: Deregulation of fibroblast growth factor receptor 3 (FGFR3) is involved in several malignancies. Its role in colorectal cancer has not been assessed before. Expression of FGFR3 in human colorectal tumour specimens was analysed using splice variant-specific real-time reverse transcriptase PCR assays. To analyse the impact of FGFR3-IIIc expression on tumour cell biology, colon cancer cell models overexpressing wild-type (WT-3b and WT3c) or dominant-negative FGFR3 variants (KD3c and KD3b) were generated by either plasmid transfection or adenoviral transduction. Although FGFR3 mRNA expression is downregulated in colorectal cancer, alterations mainly affected the FGFR3-IIIb splice variant, resulting in an increased IIIc/IIIb ratio predominantly in a subgroup of advanced tumours. Overexpression of WT3c increased proliferation, survival and colony formation in all colon cancer cell models tested, whereas WT3b had little activity. In addition, it conferred sensitivity to autocrine FGF18-mediated growth and migration signals in SW480 cells with low endogenous FGFR3-IIIc expression. Disruption of FGFR3-IIIc-dependent signalling by dominant-negative FGFR3-IIIc or small interfering RNA-mediated FGFR3-IIIc knockdown resulted in inhibition of cell growth and induction of apoptosis, which could not be observed when FGFR3-IIIb was blocked. In addition, KD3c expression blocked colony formation and migration and distinctly attenuated tumour growth in SCID mouse xenograft models. Our data show that FGFR3-IIIc exerts oncogenic functions by mediating FGF18 effects in colorectal cancer and may constitute a promising new target for therapeutic interventions.

MET kinase inhibitor SGX523 synergizes with epidermal growth factor receptor inhibitor erlotinib in a hepatocyte growth factor-dependent fashion to suppress carcinoma growth.

Abstract: The hepatocyte growth factor (HGF)-MET pathway supports several hallmark cancer traits, and it is fre-quently activated in a broad spectrum of human cancers (http://www.vai.org/met/). With the development ofmany cancer drugs targeting this pathway, there is a need for relevant in vivo model systems for preclinicalevaluation of drug efficacy. Here, we show that production of the human HGF ligand in transgenic severecombined immunodeficient mice (hHGF tg -SCID mice) enhances the growth of many MET-expressing humancarcinoma xenografts, including those derived from lung, breast, kidney, colon, stomach, and pancreas. In thismodel, the MET-specific small-molecule kinase inhibitor SGX523 partially inhibits the HGF-dependent growthof lung, breast, and pancreatic tumors. However, much greater growth suppression is achieved by combina-torial inhibition with the epidermal growth factor receptor (EGFR) kinase inhibitor erlotinib. Together, theseresults validate the hHGF tg -SCID mouse model for in vivo determination of MET sensitivity to drug inhibition.Our findings also indicate that simultaneously targeting the MET and EGFR pathways can provide synergisticinhibitory effects for the treatment of cancers in which both pathways are activated.

Epidermal growth factor receptor in relation to tumor development: EGFR‐targeted anticancer therapy

Abstract: The discovery that signaling by the epidermal growth factor receptor (EGFR) plays a key role in tumorigenesis prompted efforts to target this receptor in anticancer therapy. Two different types of EGFR-targeted therapeutic agents were subsequently developed: mAbs, such as cetuximab and panitumumab, which target the extracellular domain of the receptor, thereby inhibiting ligand-dependent EGFR signal transduction; and small-molecule tyrosine kinase inhibitors, such as gefitinib and erlotinib, which target the intracellular tyrosine kinase domain of the EGFR. Furthermore, recent clinical and laboratory studies have identified molecular markers that have the potential to improve the clinical effectiveness of EGFR-targeted therapies. This minireview summarizes the emerging role of molecular profiling in guiding the clinical use of anti-EGFR therapeutic agents.

Growth regulation and transformation of ovarian epithelium

Abstract: The discovery of peptide growth factors and cancer-causing genes (oncogenes and tumor-suppressor genes) has provided us with the exciting opportunity to begin to understand the molecular pathology of human ovarian cancer. Activation of several genes, including HER-2/ neu, myc, ras, and p53 have been described in some ovarian cancers. In addition, some protooncogenes such as the epidermal growth factor receptor (erbB) and the M-CSF receptor (fms) are expressed along with their respective ligands (peptide growth factors) in some ovarian cancers

Effects of irradiation on tumor cell survival, invasion and angiogenesis.

Abstract: Ionizing irradiation is a widely applied therapeutic method for the majority of solid malignant neoplasms, including brain tumors where, depending on localization, this might often be the only feasible primary intervention.Without doubt, it has been proved to be a fundamental tool available in the battlefield against cancer, offering a clear survival benefit in most cases. However, numerous studies have associated tumor irradiation with enhanced aggressive phenotype of the remaining cancer cells. A cell population manages to survive after the exposure, either because it receives sublethal doses and/or because it successfully utilizes the repair mechanisms. The biology of irradiated cells is altered leading to up-regulation of genes that favor cell survival, invasion and angiogenesis. In addition, hypoxia within the tumor mass limits the cytotoxicity of irradiation, whereas irradiation itself may worsen hypoxic conditions, which also contribute to the generation of resistant cells. Activation of cell surface receptors, such as the epidermal growth factor receptor, utilization of signaling pathways, and over-expression of cytokines, proteases and growth factors, for example the matrix metalloproteinases and vascular endothelial growth factor, protect tumor and non-tumor cells from apoptosis, increase their ability to invade to adjacent or distant areas, and trigger angiogenesis. This review will try to unfold the various molecular events and interactions that control tumor cell survival, invasion and angiogenesis and which are elicited or influenced by irradiation of the tumor mass, and to emphasize the importance of combining irradiation therapy with molecular targeting.

Growth factors in tumor microenvironment.

Abstract: Tumor microenvironment plays a critical role in tumor initiation and progression. Components in the microenvironment can modulate the growth of tumor cells, their ability to progress and metastasize. A major venue of communication between tumor cells and their microenvironment is through polypeptide growth factors and receptors for these growth factors. This article discusses three major classes of growth-stimulatory polypeptide growth factors and receptors for these growth factors. It also discusses how deregulation of these growth factors or their receptors can drive malignant transformation and progression.