Showing papers on "Growth factor receptor inhibitor published in 2015"

Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor

Abstract: Angiogenesis, or the formation of new capillary blood vessels, occurs primarily during human development and reproduction; however, aberrant regulation of angiogenesis is also a fundamental process found in several pathologic conditions, including cancer. As a process required for invasion and metastasis, tumor angiogenesis constitutes an important point of control of cancer progression. Although not yet completely understood, the complex process of tumor angiogenesis involves highly regulated orchestration of multiple signaling pathways. The proangiogenic signaling molecule vascular endothelial growth factor (VEGF) and its cognate receptor (VEGF receptor 2 [VEGFR-2]) play a central role in angiogenesis and often are highly expressed in human cancers, and initial clinical efforts to develop antiangiogenic treatments focused largely on inhibiting VEGF/VEGFR signaling. Such approaches, however, often lead to transient responses and further disease progression because angiogenesis is regulated by multiple pathways that are able to compensate for each other when single pathways are inhibited. The platelet-derived growth factor (PDGF) and PDGF receptor (PDGFR) and fibroblast growth factor (FGF) and FGF receptor (FGFR) pathways, for example, provide potential escape mechanisms from anti-VEGF/VEGFR therapy that could facilitate resumption of tumor growth. Accordingly, more recent treatments have focused on inhibiting multiple signaling pathways simultaneously. This comprehensive review discusses the limitations of inhibiting VEGF signaling alone as an antiangiogenic strategy, the importance of other angiogenic pathways including PDGF/PDGFR and FGF/FGFR, and the novel current and emerging agents that target multiple angiogenic pathways for the treatment of advanced solid tumors. Implications for Practice: Significant advances in cancer treatment have been achieved with the development of antiangiogenic agents, the majority of which have focused on inhibition of the vascular endothelial growth factor (VEGF) pathway. VEGF targeting alone, however, has not proven to be as efficacious as originally hoped, and it is increasingly clear that there are many interconnected and compensatory pathways that can overcome VEGF-targeted inhibition of angiogenesis. Maximizing the potential of antiangiogenic therapy is likely to require a broader therapeutic approach using a new generation of multitargeted antiangiogenic agents.

PIK3CA Mutations Are Associated With Decreased Benefit to Neoadjuvant Human Epidermal Growth Factor Receptor 2–Targeted Therapies in Breast Cancer

Abstract: Purpose We investigated whether mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) correlates with response to neoadjuvant human epidermal growth factor receptor 2 (HER2) –targeted therapies in patients with breast cancer.

Evaluating the evidence for targeting FOXO3a in breast cancer: a systematic review

Abstract: Background: Tumour cells show greater dependency on glycolysis so providing a sufficient and rapid energy supply for fast growth. In many breast cancers, estrogen, progesterone and epidermal growth factor receptor-positive cells proliferate in response to growth factors and growth factor antagonists are a mainstay of treatment. However, triple negative breast cancer (TNBC) cells lack receptor expression, are frequently more aggressive and are resistant to growth factor inhibition. Downstream of growth factor receptors, signal transduction proceeds via phosphatidylinositol 3-kinase (PI3k), Akt and FOXO3a inhibition, the latter being partly responsible for coordinated increases in glycolysis and apoptosis resistance. FOXO3a may be an attractive therapeutic target for TNBC. Therefore we have undertaken a systematic review of FOXO3a as a target for breast cancer therapeutics. Methods: Articles from NCBI were retrieved systematically when reporting primary data about FOXO3a expression in breast cancer cells after cytotoxic drug treatment. Results: Increased FOXO3a expression is common following cytotoxic drug treatment and is associated with apoptosis and cell cycle arrest. There is some evidence that metabolic enzyme expression is also altered and that this effect is also elicited in TNBC cells. FOXO3a expression serves as a positive prognostic marker, especially in estrogen (ER) receptor positive cells. Discussion: FOXO3a is upregulated by a number of receptor-dependent and -independent anti-cancer drugs and associates with apoptosis. The identification of microRNA that regulate FOXO3a directly suggest that it offers a tangible therapeutic target that merits wider evaluation.

Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer

Abstract: Purpose of reviewThe first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, are effective as first-line treatment of advanced nonsmall cell lung cancer (NSCLC) harboring activating EGFR mutations (deletions in exon 19 and exon 21 L858R muta

Epidermal growth factor signaling in transformed cells

Abstract: Members of the epidermal growth factor receptor (EGFR/ErbB) family play a critical role in normal cell growth and development. However, many ErbB family members, especially EGFR, are aberrantly expressed or deregulated in tumors and are thought to play crucial roles in cancer development and metastatic progression. In this chapter, we provide an overview of key mechanisms contributing to aberrant EGFR/ErbB signaling in transformed cells, which results in many phenotypic changes associated with the earliest stages of tumor formation, including several hallmarks of epithelial-mesenchymal transition (EMT). These changes often occur through interaction with other major signaling pathways important to tumor progression, causing a multitude of transcriptional changes that ultimately impact cell morphology, proliferation, and adhesion, all of which are crucial for tumor progression. The resulting mesh of signaling networks will need to be taken into account as new regimens are designed for targeting EGFR for therapeutic intervention. As new insights are gained into the molecular mechanisms of cross talk between EGFR signaling and other signaling pathways, including their roles in therapeutic resistance to anti-EGFR therapies, a continual reassessment of clinical therapeutic regimes and strategies will be required. Understanding the consequences and complexity of EGF signaling and how it relates to tumor progression is critical for the development of clinical compounds and establishing clinical protocols for the treatment of cancer.

GM3 and cancer.

Abstract: Our studies during the early 1970s showed that expression of GM3, the simplest ganglioside and an abundant animal cell membrane component, is reduced during malignant transformation of cells by oncogenic viruses. Levels of mRNA for GM3 synthase were reduced in avian and mammalian cells transformed by oncoprotein “v-Jun”, and overexpression of GM3 synthase in the transformed cells caused reversion from transformed to normal cell-like phenotype. GM3 has a well-documented inhibitory effect on activation of growth factor receptors (GFRs), particularly epidermal GFR (EGFR). De-N-acetyl GM3, which is expressed in some invasive human cancer cells, has an enhancing effect on EGFR activation. The important role of the sialosyl group of GM3 was demonstrated using NEU3, a plasma membrane-associated sialidase that selectively remove sialic acids from gangliosides GM3 and GD1a and is up-regulated in many human cancer cells. GM3 is highly enriched in a type of membrane microdomain termed “glycosynapse”, and forms complexes with co-localized cell signaling molecules, including Src family kinases, certain tetraspanins (e.g., CD9, CD81, CD82), integrins, and GFRs (e.g., fibroblast growth factor receptor and hepatocyte growth factor receptor c-Met). Studies by our group and others indicate that GM3 modulates cell adhesion, growth, and motility by altering molecular organization in glycosynaptic microdomains and the activation levels of co-localized signaling molecules that are involved in cancer pathogenesis.

Sirt7 Contributes to Myocardial Tissue Repair by Maintaining Transforming Growth Factor-β Signaling Pathway

Abstract: Background—Sirt7, 1 of the 7 members of the mammalian sirtuin family, promotes oncogenic transformation. Tumor growth and metastasis require fibrotic and angiogenic responses. Here, we investigated the role of Sirt7 in cardiovascular tissue repair process. Methods and Results—In wild-type mice, Sirt7 expression increased in response to acute cardiovascular injury, including myocardial infarction and hind-limb ischemia, particularly at the active wound healing site. Compared with wild-type mice, homozygous Sirt7-deficient (Sirt7−/−) mice showed susceptibility to cardiac rupture after myocardial infarction, delayed blood flow recovery after hind-limb ischemia, and impaired wound healing after skin injury. Histological analysis showed reduced fibrosis, fibroblast differentiation, and inflammatory cell infiltration in the border zone of infarction in Sirt7−/− mice. In vitro, Sirt7−/− mouse–derived or Sirt7 siRNA–treated cardiac fibroblasts showed reduced transforming growth factor-β signal activation and low ...

Mechanistic basis and clinical relevance of the role of transforming growth factor-β in cancer.

Abstract: Transforming growth factor-β (TGF-β) is a key factor in cancer development and progression. TGF-β can suppress tumorigenesis by inhibiting cell cycle progression and stimulating apoptosis in early stages of cancer progression. However, TGF-β can modulate cancer-related processes, such as cell invasion, distant metastasis, and microenvironment modification that may be used by cancer cells to their advantage in late stages. Corresponding mechanisms include angiogenesis promotion, anti-tumor immunity suppression, and epithelial-to-mesenchymal transition (EMT) induction. The correlation between TGF-β expression and cancer prognosis has also been extensively investigated. Results suggest that TGF-β pathway can be targeted to treat cancer; as such, the feasibility of this treatment is investigated in clinical trials.

Minireview: Were the IGF Signaling Inhibitors All Bad?

Abstract: Preclinical studies in the 1980s defined a role for IGF signaling in the development and sustainability of the malignant process. Subsequently, antibody, tyrosine kinase, and ligand inhibitors of the IGF receptor were manufactured. In the past decade, numerous clinical trials have tested the efficacy of IGF receptor inhibitors in the treatment of advanced tumors. Early-phase trials in heavily pretreated populations showed promise with complete or partial responses in a few patients and stable disease in many more. Unfortunately, the results of the early-phase trials did not pan out to later-phase trials. The lack of use of biomarkers to define subsets of patients that may benefit from IGF receptor blockade and compensatory signaling via other growth factor receptors such as the insulin, GH, and epidermal growth factor receptors may have played a role in the lack of efficacy of IGF receptor inhibition in phase III trials. Although these trials failed to show benefit, the trials have revealed previously unknown knowledge regarding the complex nature of IGF signaling. The knowledge obtained from these trials will be useful in designing future trials studying inhibitors of growth factor signaling.

Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer

Abstract: The VEGF pathway has become an important therapeutic target in lung cancer, where VEGF has long been established as a potent pro-angiogenic growth factor expressed by many types of tumors. While Bevacizumab (Avastin) has proven successful in increasing the objective tumor response rate and in prolonging progression and overall survival in patients with NSCLC, the survival benefit is however relatively short and the majority of patients eventually relapse. The current use of tyrosine kinase inhibitors alone and in combination with chemotherapy has been underwhelming, highlighting an urgent need for new targeted therapies. In this study, we examined the mechanisms of VEGF-mediated survival in NSCLC cells and the role of the Neuropilin receptors in this process. NSCLC cells were screened for expression of VEGF and its receptors. The effects of recombinant VEGF and its blockade on lung tumor cell proliferation and cell cycle were examined. Phosphorylation of Akt and Erk1/2 proteins was examined by high content analysis and confocal microscopy. The effects of silencing VEGF on cell proliferation and survival signaling were also assessed. A Neuropilin-1 stable-transfected cell line was generated. Cell growth characteristics in addition to pAkt and pErk1/2 signaling were studied in response to VEGF and its blockade. Tumor growth studies were carried out in nude mice following subcutaneous injection of NP1 over-expressing cells. Inhibition of the VEGF pathway with anti-VEGF and anti-VEGFR-2 antibodies or siRNA to VEGF, NP1 and NP2 resulted in growth inhibition of NP1 positive tumor cell lines associated with down-regulation of PI3K and MAPK kinase signaling. Stable transfection of NP1 negative cells with NP1 induced proliferation in vitro, which was further enhanced by exogenous VEGF. In vivo, NP1 over-expressing cells significantly increased tumor growth in xenografts compared to controls. Our data demonstrate that VEGF is an autocrine growth factor in NSCLC signaling, at least in part, through NP1. Targeting this VEGF receptor may offer potential as a novel therapeutic approach and also support the evaluation of the role of NP1 as a biomarker predicting sensitivity or resistance to VEGF and VEGFR-targeted therapies in the clinical arena.

Thyroid Hormone, Hormone Analogs, and Angiogenesis

Abstract: Modulation by thyroid hormone and hormone analogs of angiogenesis in the heart after experimental infarction, and in other organs, has been appreciated for decades. Description of a plasma membrane receptor for thyroid hormone on the extracellular domain of integrin αvβ3 on endothelial cells has revealed the complexity of the nongenomic regulation of angiogenesis by the hormone. From αvβ3, the hormone directs transcription of specific vascular growth factor genes, regulates growth factor receptor/growth factor interactions and stimulates endothelial cell migration to a vitronectin cue; these actions are implicated experimentally in tumor-relevant angiogenesis and angioproliferative pulmonary hypertension. Derived from L-thyroxine (T4), tetraiodothyroacetic acid (tetrac) can be covalently bound to a polymer and as Nanotetrac acts exclusively at the hormone receptor on αvβ3 to block actions of T4 and 3,5,3′-triiodo-L-thyronine (T3) on angiogenesis. Other antiangiogenic actions of Nanotetrac include disruption of crosstalk between integrin αvβ3 and adjacent cell surface vascular growth factor receptors, resulting in disordered vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF; FGF2) actions at their respective plasma membrane receptors. From αvβ3, Nanotetrac also downregulates expression of VEGFA and epidermal growth factor receptor (EGFR) genes, upregulates transcription of the angiogenesis suppressor gene, thrombospondin 1 (THBS1; TSP1) and decreases cellular abundance of Ang-2 protein and matrix metalloproteinase-9. Existence of this receptor provides new insights into the multiple mechanisms by which thyroid hormone and hormone analogs may regulate angiogenesis at the molecular level. The receptor also offers pharmacological opportunities for interruption of pathological angiogenesis via integrin αvβ3. © 2016 American Physiological Society. Compr Physiol 6:353-362, 2016.

Insulin-Like Growth Factor and Epidermal Growth Factor Signaling in Breast Cancer Cell Growth: Focus on Endocrine Resistant Disease

Abstract: Breast cancer is the most common type of cancer for women worldwide with a lifetime risk amounting to a staggering total of 10%. It is well established that the endogenous synthesis of insulin-like growth factor (IGF) and epidermal growth factor (EGF) polypeptide growth factors are closely correlated to malignant transformation and all the steps of the breast cancer metastatic cascade. Numerous studies have demonstrated that both estrogens and growth factors stimulate the proliferation of steroid-dependent tumor cells, and that the interaction between these signaling pathways occurs at several levels. Importantly, the majority of breast cancer cases are estrogen receptor- (ER-) positive which have a more favorable prognosis and pattern of recurrence with endocrine therapy being the backbone of treatment. Unfortunately, the majority of patients progress to endocrine therapy resistant disease (acquired resistance) whereas a proportion of patients may fail to respond to initial therapy (de novo resistance). The IGF-I and EGF downstream signaling pathways are closely involved in the process of progression to therapy resistant disease. Modifications in the bioavailability of these growth factors contribute critically to disease progression. In the present review therefore, we will discuss in depth how IGF and EGF signaling participate in breast cancer pathogenesis and progression to endocrine resistant disease.

The stem cell transcription factor ZFP57 induces IGF2 expression to promote anchorage-independent growth in cancer cells.

Abstract: Several common biological properties between cancer cells and embryonic stem (ES) cells suggest the possibility that some genes expressed in ES cells might have important roles in cancer cell growth. The transcription factor ZFP57 is expressed in self-renewing ES cells and its expression level decreases during ES cell differentiation. This study showed that ZFP57 is involved in the anchorage-independent growth of human fibrosarcoma HT1080 cells in soft agar. ZFP57 overexpression enhanced, whereas knockdown suppressed, HT1080 tumor formation in nude mice. Furthermore, ZFP57 regulates the expression of insulin-like growth factor 2 (IGF2), which has a critical role in ZFP57-induced anchorage-independent growth. ZFP57 also promotes anchorage-independent growth in ES cells and immortal fibroblasts. Finally, immunohistochemical analysis revealed that ZFP57 is overexpressed in human cancer clinical specimens. Taken together, these results suggest that the ES-specific transcription factor ZFP57 is a novel oncogene.

Fibroblast growth factor receptor 2 fusions as a target for treating cholangiocarcinoma.

Abstract: Purpose of review This review will cover the role of the fibroblast growth factor pathway in the pathogenesis, targeted therapy potential and prognostic value in patients with cholangiocarcinoma (CCA).

Molecular concept in human oral cancer.

Abstract: The incidence of oral cancer remains high in both Asian and Western countries. Several risk factors associated with development of oral cancer are now well-known, including tobacco chewing, smoking, and alcohol consumption. Cancerous risk factors may cause many genetic events through chromosomal alteration or mutations in genetic material and lead to progression and development of oral cancer through histological progress, carcinogenesis. Oral squamous carcinogenesis is a multistep process in which multiple genetic events occur that alter the normal functions of proto-oncogenes/oncogenes and tumor suppressor genes. Furthermore, these gene alterations can deregulate the normal activity such as increase in the production of growth factors (transforming growth factor-α [TGF-α], TGF-β, platelet-derived growth factor, etc.) or numbers of cell surface receptors (epidermal growth factor receptor, G-protein-coupled receptor, etc.), enhanced intracellular messenger signaling and mutated production of transcription factors (ras gene family, c-myc gene) which results disturb to tightly regulated signaling pathways of normal cell. Several oncogenes and tumor suppressor genes have been implicated in oral cancer especially cyclin family, ras, PRAD-1, cyclin-dependent kinase inhibitors, p53 and RB1. Viral infections, particularly with oncogenic human papilloma virus subtype (16 and 18) and Epstein-Barr virus have tumorigenic effect on oral epithelia. Worldwide, this is an urgent need to initiate oral cancer research programs at molecular and genetic level which investigates the causes of genetic and molecular defect, responsible for malignancy. This approach may lead to development of target dependent tumor-specific drugs and appropriate gene therapy.

Insulin-Like Growth Factor Binding Proteins--an Update.

Abstract: The insulin-like growth factor (IGF) system is essential for normal growth and development, and its perturbation is implicated in a number of diseases. IGF activity is finely regulated by a family of six high-affinity IGF binding proteins (IGFBPs). 1GFBPs usually inhibit IGF actions but may enhance them under certain conditions. Additionally, IGFBPs bind non-IGF ligands in the extracellular space, cell membrane, cytoplasm and nucleus, thereby modulating cell proliferation, survival and migration in an IGF-independent manner. IGFBP activity is regulated by transcriptional mechanisms as well as by post-translational modifications and proteolysis. Understanding the balance between the various actions of IGFBPs in vivo may lead to novel insights into disease processes and possible IGFBP-based therapeutics.

Targeting the insulin-like growth factor receptor and Src signaling network for the treatment of non-small cell lung cancer

Abstract: Therapeutic interventions in the insulin-like growth factor receptor (IGF-1R) pathway were expected to provide clinical benefits; however, IGF-1R tyrosine kinase inhibitors (TKIs) have shown limited antitumor efficacy, and the mechanisms conveying resistance to these agents remain elusive. The expression and activation of the IGF-1R and Src were assessed via the analysis of a publicly available dataset, as well as immunohistochemistry, Western blotting, RT-PCR, and in vitro kinase assays. The efficacy of IGF-1R TKIs alone or in combination with Src inhibitors was analyzed using MTT assays, colony formation assays, flow cytometric analysis, and xenograft tumor models. The co-activation of IGF-1R and Src was observed in multiple human NSCLC cell lines as well as in a tissue microarray (n = 353). The IGF-1R and Src proteins mutually phosphorylate on their autophosphorylation sites. In high-pSrc-expressing NSCLC cells, linsitinib treatment initially inactivated the IGF-1R pathway but led a Src-dependent reactivation of downstream effectors. In low-pSrc-expressing NSCLC cells, linsitinib treatment decreased the turnover of the IGF-1R and Src proteins, ultimately amplifying the reciprocal co-activation of IGF-1R and Src. Co-targeting IGF-1R and Src significantly suppressed the proliferation and tumor growth of both high-pSrc-expressing and low-pSrc-expressing NSCLC cells in vitro and in vivo and the growth of patient-derived tissues in vivo. Reciprocal activation between Src and IGF-1R occurs in NSCLC. Src causes IGF-1R TKI resistance by acting as a key downstream modulator of the cross-talk between multiple membrane receptors. Targeting Src is a clinically applicable strategy to overcome resistance to IGF-1R TKIs.

Growth hormone, insulin-like growth factor system and carcinogenesis

Abstract: The growth hormone (GH) and insulin-like growth factor (IGF) system plays an important role in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis. In terms of cell cycle regulation, the GH-IGF system induces signalling pathways for cell growth that compete with other signalling systems that result in cell death; thus the final effect of these opposed forces is critical for normal and abnormal cell growth. The association of the GH-IGF system with carcinogenesis has long been hypothesised, mainly based on in vitro studies and the use of a variety of animal models of human cancer, and also on epidemiological and clinical evidence in humans. While ample experimental evidence supports a role of the GH-IGF system in tumour promotion and progression, with several of its components being currently tested as central targets for cancer therapy, the strength of evidence from patients with acromegaly, GH deficiency, or treated with GH is much weaker. In this review, we will attempt to consolidate this data. (Endokrynol Pol 2016; 67 (4): 414-426).

Down-regulating HIF-1α by lentivirus-mediated shRNA for therapy of triple negative breast cancer.

Abstract: Hypoxia is associated with poor response to treatment in various cancers. Hypoxia inducible factor 1 (HIF-1) is a major transcription factor that mediates adaptation of cancer cells to a hypoxic environment and regulates many genes that are involved in key cellular functions, including cell immortalization, stem cell maintenance, autocrine growth/survival, angiogenesis, invasion/metastasis, and resistance to chemotherapy. HIF-1α has been considered as an attractive therapeutic target for cancer treatment, but there is limited success in this research field. In the present study, we designed a recombinant lentivirus containing HIF-1α siRNA, developed stably transfected cell lines, and tested the anticancer effects of the siRNA on cancer cells in vitro and in vivo. Our results indicated that the stable downregulation of HIF-1α reversed chemoresistance, inhibited proliferation, migration and invasion of cancer cells, and slowed down the tumor growth in breast cancer xenograft models. In conclusion, the recombinant lentivirus containing HIF-1α siRNA provides a new avenue for developing novel therapy for triple negative breast cancer.

Lewis(y) Promotes Migration of Oral Cancer Cells by Glycosylation of Epidermal Growth Factor Receptor

Abstract: Aberrant glycosylation changes normal cellular functions and represents a specific hallmark of cancer. Lewisy (Ley) carbohydrate upregulation has been reported in a variety of cancers, including or...

Inhibition of intracerebral glioblastoma growth by targeting the insulin-like growth factor 1 receptor involves different context-dependent mechanisms.

Abstract: Signaling by type 1 insulin-like growth factor receptor (IGF-1R) plays a role in the formation, maintenance, and progression of many diverse tumor types.1 In the central nervous system, IGF-1R has been implicated in fetal and postnatal brain development as well as in brain tumor growth.2 Overexpression of IGF-1R and its ligands IGF-1 and IGF-2 was detected in human astrocytomas, and activated IGF-1R signaling indicates that this pathway contributes to tumor progression.3–7 Furthermore, resistance to treatment with epidermal growth factor receptor tyrosine kinase inhibitors in glioblastoma cells can be mediated by IGF-1R activation.8–10 IGF-1R is a transmembrane receptor tyrosine kinase that activates the signaling pathways of phosphatidylinositol-3 kinase/Akt and Ras-Raf–mitogen-activated protein kinase.2 It belongs to the insulin receptor (IR) family, which includes IR, IGF-1R, the hybrid receptor IGF-1R/IR, and IGF-2R. IGF-1R is primarily activated by IGF-1 and IGF-2, but superphysiological levels of insulin can also stimulate the receptor.2 Blockade of IGF-1R signaling can induce multimodal antitumor effects, such as pro-apoptotic, antiproliferative, anti-invasive and anti-angiogenic activity. Different types of IGF-1R inhibitors have been developed, including antibodies and low-molecular-weight tyrosine kinase inhibitors.11 Phase II clinical trials with monoclonal anti–IGF-1R antibodies have demonstrated sustained responses in a subset of patients with Ewing sarcoma and thymoma; however, phase III trials with colorectal or lung cancer patients failed to show clinical benefit.11 In pilot studies of patients with malignant gliomas, IGF-1R antisense oligonucleotide strategies were tested, but responses were only moderate,12 so that this strategy has not yet been developed beyond phase I. In an ongoing phase I/II trial on patients with recurrent malignant astrocytoma, the efficacy of picropodophyllin, a cyclolignan that inhibits IGF-1R activation, is being evaluated (http://www.clinicaltrials.gov/ct2/show/NCT01721577). Picropodophyllin has demonstrated antitumor activity in several glioma models13; however, it possesses also nonspecific activities. IMC-A12 (cixutumumab) is a fully human monoclonal antibody directed against IGF-1R. It binds IGF-1R with high affinity, blocks its interaction with IGF-1 and IGF-2, and induces receptor internalization and degradation.14,15 IMC-A12 also binds hybrid IGF-1R/IR receptors on tumor cells but not IRs. IMC-A12 has demonstrated growth inhibition in vivo of several tumor types, such as breast, renal, and pancreatic cancer, and has been tested in phase II clinical cancer trials on patients with sarcomas and adrenocortical carcinomas.16,17 In the present study, we demonstrate that the IMC-A12 antibody potently inhibits glioblastoma progression in 2 different orthotopic in vivo xenograft models. Interestingly, we identified different mechanisms of tumor growth inhibition. In a glioblastoma stemlike (GS) cell line–derived xenograft model, which captures the infiltrative aspect of the disease, growth inhibition was achieved by direct inhibition of tumor cell proliferation and invasion. In contrast, in a non-invasive, highly angiogenesis-dependent model, growth inhibition was apparently achieved by a striking reduction of tumor vascularization.

Therapeutic Targeting of Fibroblast Growth Factor Receptors in Gastric Cancer

Abstract: Chemotherapy has become the global standard treatment for patients with metastatic or unresectable gastric cancer (GC), although outcomes remain unfavorable. Many molecular-targeted therapies inhibiting signaling pathways of various tyrosine kinase receptors have been developed, and monoclonal antibodies targeting human epidermal growth factor receptor 2 (HER2) have become standard therapy for HER2-positive GC. An inhibitor of vascular endothelial growth factor receptor 2 or MET has also produced promising results in patients with GC. Fibroblast growth factor receptors (FGFR) play key roles in tumor growth via activated signaling pathways in GC. Genomic amplification of FGFR2 leads to the aberrant activation found in GC tumors and is related to survival in patients with GC. This review discusses the clinical relevance of FGFR in GC and examines FGFR as a potential therapeutic target in patients with GC. Preclinical studies in animal models suggest that multitargeted tyrosine kinase inhibitors (TKIs), including FGFR inhibitor, suppress tumor cell proliferation and delay tumor progression. Several TKIs are now being evaluated in clinical trials as treatment for metastatic or unresectable GC harboring FGFR2 amplification.

Role of G protein-coupled receptors (GPCR), matrix metalloproteinases 2 and 9 (MMP2 and MMP9), heparin-binding epidermal growth factor-like growth factor (hbEGF), epidermal growth factor receptor (EGFR), erbB2, and insulin-like growth factor 1 receptor (IGF-1R) in trenbolone acetate-stimulated bovine satellite cell proliferation.

Abstract: Implanting cattle with steroids significantly enhances feed efficiency, rate of gain, and muscle growth. However, the mechanisms responsible for these improvements in muscle growth have not been fully elucidated. Trenbolone acetate (TBA), a testosterone analog, has been shown to increase proliferation rate in bovine satellite cell (BSC) cultures. The classical genomic actions of testosterone have been well characterized; however, our results indicate that TBA may also initiate a quicker, nongenomic response that involves activation of G protein-coupled receptors (GPCR) resulting in activation of matrix metalloproteinases 2 and 9 (MMP2 and MMP9) that release membrane-bound heparin-binding epidermal growth factor-like growth factor (hbEGF), which then binds to and activates the epidermal growth factor receptor (EGFR) and/or erbB2. Furthermore, the EGFR has been shown to regulate expression of the IGF-1 receptor (IGF-1R), which is well known for its role in modulating muscle growth. To determine whether this nongenomic pathway is potentially involved in TBA-stimulated BSC proliferation, we analyzed the effects of treating BSC with guanosine 5'-O-2-thiodiphosphate (GDPβS), an inhibitor of all GPCR; a MMP2 and MMP9 inhibitor (MMPI); CRM19, a specific inhibitor of hbEGF; AG1478, a specific EGFR tyrosine kinase inhibitor; AG879, a specific erbB2 kinase inhibitor; and AG1024, an IGF-1R tyrosine kinase inhibitor on TBA-stimulated proliferation rate (H-thymidine incorporation). Assays were replicated at least 9 times for each inhibitor experiment using BSC cultures obtained from at least 3 different animals. Bovine satellite cell cultures were obtained from yearling steers that had no previous exposure to androgenic or estrogenic compounds. As expected, BSC cultures treated with 10 n TBA showed ( < 0.05) increased proliferation rate when compared with control cultures. Additionally, treatment with 5 ng hbEGF/mL stimulated proliferation in BSC cultures ( < 0.05). Treatment with GDPβS, MMPI, CRM197, AG1024, AG1478, and/or AG879 all suppressed ( < 0.05) TBA-induced increases in proliferation. These data indicate that TBA likely initiates a nongenomic response involving GPCR, MMP2 and MMP9, hbEGF, EGFR, erbB2, and IGF-1R, which may play a role in TBA-mediated increases in BSC proliferation.

miR-126 regulates platelet-derived growth factor receptor-α expression and migration of primary human osteoblasts.

Abstract: Adequate vascularization is an essential requirement for bone development, fracture healing and bone tissue engineering. We have previously described the coculture of primary human osteoblasts (hOBs) and human endothelial cells (HUVECs), designed to investigate the interactions between these cells. In this system, we showed that cocultivation of these two cell types leads to a downregulation of platelet-derived growth factor receptor-α (PDGFR-α) in hOBs, which was a consequence of reduced mRNA stability. In the current study we investigated the possible involvement of microRNAs in this process. Firstly, we performed a microarray analysis of osteoblastic miRNAs following cocultivation with HUVECs, revealing an upregulation of miR-126. This result was confirmed by RT-qPCR, and we observed that the increase is dependent on direct cell-to-cell contacts. Gain-of-function and loss-of-function experiments showed that miR-126 is a negative regulator of PDGFR-α mRNA. Additionally, migration of hOBs was inhibited by miR-126 overexpression and stimulated by miR-126 inhibition. Addition of PDGFR-α blocking antibody to hOB culture also inhibited hOB migration. There was no effect of miR-126 modulation on osteoblast proliferation, apoptosis rate or differentiation. In conclusion, we report that the miR-126/PDGFR-α system regulates the migratory behavior of human osteoblasts, without exerting effects on cell survival and differentiation.

Targeting fibroblast growth factor receptor (FGFR) pathway in renal cell carcinoma.

Abstract: Fibroblast growth factor receptor (FGFR) pathway is involved in driving vascular endothelial growth factor (VEGF)-independent tumor angiogenesis, as a compensatory mechanism to escape VEGF-targeted therapies. Therefore, targeting FGF/FGFR axis seems to be a promising strategy in order to inhibit tumor angiogenesis and reduce resistance to VEGF receptor-tyrosine kinase inhibitors. This editorial is focused on the role of FGF/FGFR pathway in renal cell carcinoma and on the ongoing trials of emerging agents targeting this axis.