VEGF-RII Influences the Prognosis of Pancreatic Cancer

Büchler, Peter; Reber, Howard A.; Büchler, Markus W.; Frieß, Helmut; Hines, Oscar J.

doi:10.1097/00000658-200212000-00006

Cited by 81 publications

(67 citation statements)

References 39 publications

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“…For example, substantial evidence suggests that expression of VEGF is regulated mainly by hypoxia, which is a common feature of most solid tumors, including pancreatic cancers (21). VEGFR was found on the endothelial cells of blood vessels of pancreatic cancer in vivo (22), influencing the prognosis of patients (8). Previous studies have also suggested that high levels of EGFR predict for intrinsic radioresistance and poor clinical prognosis (6,23).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, a recent study showed that patients with pancreatic cancer overexpressing EGFR had shorter survival (6). Similarly, overexpression of vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) correlates with increased tumor growth rate, microvessel density, tumor metastatic potential, and poor prognosis in a variety of malignancies, including pancreatic cancer (7,8).…”

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confidence: 99%

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Synergistic Antitumor Activity of ZD6474, An Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, with Gemcitabine and Ionizing Radiation against Pancreatic Cancer

Bianco¹,

Giovannetti

Ciardiello³

et al. 2006

Clinical Cancer Research

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Purpose: Standard treatments have modest effect against pancreatic cancer, and current research focuses on agents targeting molecular pathways involved in tumor growth and angiogenesis. This study investigated the interactions between ZD6474, an inhibitor of tyrosine kinase activities of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor (EGFR), gemcitabine, and ionizing radiation in human pancreatic cancer cells and analyzed the molecular mechanisms underlying this combination. Experimental Design: ZD6474, ionizing radiation, and gemcitabine, alone or in combination, were given in vitro to MIA PaCa-2, PANC-1, and Capan-1cells and in vivo to MIA PaCa-2 tumor xenografts. The effects of treatments were studied by the evaluation of cytotoxicity, apoptosis, cell cycle, EGFR and Akt phosphorylation, modulation of gene expression of enzymes related to gemcitabine activity (deoxycytidine kinase and ribonucleotide reductase), as well as vascular endothelial growth factor immunohistochemistry and microvessel count. Results: In vitro, ZD6474 dose dependently inhibited cell growth, induced apoptosis, and synergistically enhanced the cytotoxic activity of gemcitabine and ionizing radiation. Moreover, ZD6474 inhibited phosphorylation of EGFR and Akt and triggered cell apoptosis. PCR analysis showed that ZD6474 increased the ratio between gene expression of deoxycytidine kinase and ribonucleotide reductase. In vivo, ZD6474 showed significant antitumor activity alone and in combination with radiotherapy and gemcitabine, and the combination of all three modalities enhanced MIA PaCA-2 tumor growth inhibition compared with gemcitabine alone. Conclusions: ZD6474 decreases EGFR and Akt phosphorylation, enhances apoptosis, favorably modulates gene expression in cancer cells, and acts synergistically with gemcitabine and radiotherapy to inhibit tumor growth. These findings support the investigation of this combination in the clinical setting.Pancreatic cancer is a highly malignant illness that has steadily increased in incidence over recent decades, and it is now the fourth leading cause of death from cancer in the Western world. Despite this, there has been little improvement in prognosis over the past 20 years (1). Due to the delay of clinical symptoms, pancreatic cancer is usually detected at an advanced stage, and survival ranges between 4 and 6 months after diagnosis. Moreover, because of its aggressive biological behavior, this malignancy has a grim prognosis even following surgical resection, and the 5-year survival for all stages of the disease remains below 4% (2). Therefore, pancreatic cancer represents a clinical challenge and novel therapeutic approaches are warranted.Several studies showed that pancreatic cancer is characterized by dysregulation of molecular mechanisms involved in cell proliferation, invasiveness, and angiogenesis (3). Epidermal growth factor receptor (EGFR) is a key driver of cell proliferation, and

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Synergistic Antitumor Activity of ZD6474, An Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, with Gemcitabine and Ionizing Radiation against Pancreatic Cancer

Bianco¹,

Giovannetti

Ciardiello³

et al. 2006

Clinical Cancer Research

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“…19 The rationale for analyzing PKC412 in pancreatic cancer is based on its broad inhibitory spectrum of numerous critical angiogenic and mitogenic pathways, previously shown to be altered in pancreatic cancer. 6,20,21 Preliminary data on FLT3 expression suggest that this receptor may play a role in hematopoietic cell lineages and their stem cells, but almost nothing is known about its role in solid tumor growth. Therefore, we analyzed expression of FLT3 in pancreatic cancer and assayed a large number of pancreatic cancer cell lines for activating mutations in the FLT3 gene.…”

Section: Results Flt3 Expression Is Down-regulated In Pancreatic Canmentioning

confidence: 99%

“…Without any doubt, the tumor microenvironment and changes in gene expression profiles may result in activation of oncogenic signaling pathways including tyrosine kinase activation. [5][6][7] For some cancer entities, identification of key genetic alterations leads to targeted therapy. Among the receptor tyrosine kinases that can be constitutively activated by distinct genetic mutations is the FLT3…”

Section: Methods Flt3 Expression Was Analyzed In 18 Pancreatic Cancementioning

confidence: 99%

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PKC 412 small‐molecule tyrosine kinase inhibitor

Fitori

Büchler

et al. 2007

Cancer

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BACKGROUND. PKC412 is a kinase inhibitor that blocks protein kinase C (PKC), vascular endothelial growth factor receptors, platelet‐derived growth factor receptor FLT3, and other class III receptor tyrosine kinases. The enthusiasm for this compound is based on its inhibitory effect even in the case of FLT3 mutations. The aim of this study was to analyze the role of FLT3 in pancreatic cancer and to study the biological activity of combined inhibition of neovascularization and mitogenesis in this disease. METHODS. FLT3 expression was analyzed in 18 pancreatic cancer specimens by real‐time quantitative polymerase chain reaction (RTQ‐PCR) and immunohistochemistry. Sixteen pancreatic cancer cell lines were screened for ITD and D835 point mutations of the FLT3 gene. MTT assays and anchorage‐independent growth assays were used to study cell growth. Flow cytometry was used for cell cycle analysis and apoptosis quantification. In vivo AsPC‐1 and HPAF‐II cells were used for orthotopic tumor modeling. Immunohistochemistry was used to quantify tumor angiogenesis. RESULTS. FLT3 expression is down‐regulated in pancreatic cancer. Activating FLT3 mutations (ITD, D835) were not detectable in any of the pancreatic cancer cell lines. Cell growth was significantly inhibited as cell‐cycle progression was reduced and programmed cell death increased. In vivo PKC412 therapy resulted in a significant inhibition of orthotopic tumor growth with abrogation of tumor angiogenesis. CONCLUSIONS. These data highlight that PKC412 may be a new compound in target therapy of inoperable pancreatic cancer patients and suggest a potential role for the combined use of broad spectrum kinase inhibitors in the management of these patients. Cancer 2007. © 2007 American Cancer Society.

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