Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 11 to 20 of 29

Publication Record

Connections

Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors.
Lockhart AC, Rothenberg ML, Dupont J, Cooper W, Chevalier P, Sternas L, Buzenet G, Koehler E, Sosman JA, Schwartz LH, Gultekin DH, Koutcher JA, Donnelly EF, Andal R, Dancy I, Spriggs DR, Tew WP
(2010) J Clin Oncol 28: 207-14
MeSH Terms: Adult, Aged, Angiogenesis Inhibitors, Female, Humans, Infusions, Intravenous, Male, Maximum Tolerated Dose, Middle Aged, Neoplasms, Protein Kinase Inhibitors, Receptors, Vascular Endothelial Growth Factor, Recombinant Fusion Proteins, Vascular Endothelial Growth Factor A
Show Abstract · Added February 28, 2014
PURPOSE - Vascular endothelial growth factor (VEGF) Trap (aflibercept) is an angiogenesis inhibitor comprising portions of the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G. This phase I study was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of VEGF Trap administered intravenously (IV) every 2 weeks.
PATIENTS AND METHODS - Patients with refractory solid tumors or non-Hodgkin's lymphoma with adequate organ function were eligible. Pharmacokinetic/pharmacodynamic markers included measurement of plasma VEGF bound to VEGF Trap and free VEGF Trap. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was incorporated to measure the biologic effects of the drug on tumor vascularity and permeability.
RESULTS - The study enrolled 47 patients at doses ranging from 0.3 to 7.0 mg/kg IV every 2 weeks. Dose-limiting toxicities were rectal ulceration and proteinuria at the 7.0 mg/kg dose. Other mechanism-specific toxicities included hypertension. On the basis of these observations and on pharmacokinetics, the recommended phase II dose of VEGF Trap as a single agent is 4 mg/kg every 2 weeks. Three RECIST (Response Evaluation Criteria in Solid Tumors) -defined partial responses were observed, one at the 3.0 mg/kg and two at the 7.0 mg/kg dose level. Maximum plasma concentration of free VEGF Trap increased proportionally with dose. Maximal VEGF-bound VEGF Trap complex levels were reached at doses > or = 2.0 mg/kg. Changes in volume transfer constant measured by DCE-MRI at baseline and at 24 hours after administration indicate a possible dose-related change in this pharmacodynamic marker.
CONCLUSION - IV VEGF Trap was well tolerated at the dose levels tested. Pharmacodynamic and pharmacokinetic markers were indicative of VEGF blockade.
0 Communities
2 Members
0 Resources
14 MeSH Terms
The role of VHL in clear-cell renal cell carcinoma and its relation to targeted therapy.
Clark PE
(2009) Kidney Int 76: 939-45
MeSH Terms: Animals, Antibodies, Monoclonal, Antineoplastic Agents, Aryl Hydrocarbon Receptor Nuclear Translocator, Carcinoma, Renal Cell, Drug Design, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney Neoplasms, Protein Kinase Inhibitors, Protein Kinases, Receptors, Vascular Endothelial Growth Factor, Signal Transduction, TOR Serine-Threonine Kinases, Translational Medical Research, Treatment Outcome, Vascular Endothelial Growth Factor A, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added May 27, 2014
The basic biology underlying the development of clear-cell renal cell carcinoma (ccRCC) is critically dependent on the von Hippel-Lindau gene (VHL), whose protein product is important in the cell's normal response to hypoxia. Aberrations in VHL's function, either through mutation or promoter hypermethylation, lead to accumulation of the transcriptional regulatory molecule, hypoxia-inducible factor alpha (HIFalpha). HIFalpha can then dimerize with HIFbeta and translocate to the nucleus, where it will transcriptionally upregulate a series of hypoxia-responsive genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and others. Binding of these ligands to their cognate receptors activates a series of kinase- dependent signaling pathways, including the RAF-MEK-ERK and phosphatidylinositol-3 kinase-AKT-mTOR pathways. Targeted agents developed and now approved for use in advanced ccRCC include humanized monoclonal antibodies against VEGF, small-molecule tyrosine kinase inhibitors, and inhibitors of mTOR. Understanding the biology of ccRCC is critical in understanding the current therapy for the disease and in developing novel therapeutics in the future. This review will provide an overview of the genetics of ccRCC, with an emphasis on how this has informed the development of the targeted therapeutics for this disease.
0 Communities
1 Members
0 Resources
19 MeSH Terms
Treatment of advanced renal cell carcinoma with the combination bevacizumab/erlotinib/imatinib: a phase I/II trial.
Hainsworth JD, Spigel DR, Sosman JA, Burris HA, Farley C, Cucullu H, Yost K, Hart LL, Sylvester L, Waterhouse DM, Greco FA
(2007) Clin Genitourin Cancer 5: 427-32
MeSH Terms: Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Bevacizumab, Carcinoma, Renal Cell, ErbB Receptors, Erlotinib Hydrochloride, Female, Humans, Imatinib Mesylate, Kidney Neoplasms, Male, Middle Aged, Piperazines, Pyrimidines, Quinazolines, Receptors, Platelet-Derived Growth Factor, Receptors, Vascular Endothelial Growth Factor
Show Abstract · Added March 20, 2014
PURPOSE - The aim of this study was to evaluate the efficacy and toxicity of imatinib, a platelet-derived growth factor-beta receptor antagonist, when added to the combination bevacizumab/erlotinib in the treatment of patients with advanced clear cell renal carcinoma.
PATIENTS AND METHODS - Ninety-four patients with metastatic clear cell renal carcinoma were treated with bevacizumab 10 mg/kg intravenously every 2 weeks, erlotinib 150 mg orally daily, and imatinib 400 mg orally daily. Patients were reevaluated after 8 weeks of treatment; patients with objective response or stable disease (SD) continued to receive treatment until they experienced tumor progression.
RESULTS - Fifteen of 88 evaluable patients (17%; 95% confidence interval, 10%-26%) had partial responses, whereas an additional 54 patients (61%) had SD. The median progression-free and overall survival for all patients was 8.9 months and 17.2 months, respectively. The addition of imatinib markedly increased toxicity compared with the bevacizumab/erlotinib regimen; the most common grade 3/4 toxicities were diarrhea, rash, and fatigue.
CONCLUSION - Bevacizumab/erlotinib/imatinib was unacceptably toxic in this group of patients. Inhibition of the PDGF receptor (PDGFR) with imatinib did not appear to improve efficacy compared retrospectively with the results of treatment with bevacizumab/erlotinib. The importance of PDGFR inhibition in the treatment of advanced clear cell renal carcinoma remains unclear. Further development of this particular combination is not planned or recommended.
0 Communities
1 Members
0 Resources
22 MeSH Terms
Inhibition of angiogenesis in the treatment of non-small cell lung cancer.
Keedy VL, Sandler AB
(2007) Cancer Sci 98: 1825-30
MeSH Terms: Angiogenesis Inhibitors, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Neovascularization, Pathologic, Receptors, Vascular Endothelial Growth Factor
Show Abstract · Added March 11, 2014
Angiogenesis and its role in the growth and development of metastases has become a topic of increasing importance. In non-small cell lung cancer (NSCLC), vascular endothelial growth factor (VEGF) plays an important role in angiogenesis, growth of the primary tumor, and development of metastases. In addition, elevated expression in tissue samples is a negative prognostic feature. For these reasons, VEGF is a worthy target for novel therapies. Recent clinical trials have shown that the anti-VEGF monoclonal antibody bevacizumab adds to the effect of chemotherapy in the metastatic setting. Hypertension and proteinuria are, as expected, commonly seen in this patient population, but the unexpected toxicity of life-threatening hemoptysis has also been observed. This makes careful patient selection especially important for this class of drugs. Our understanding of the VEGF pathway is increasing, as are the number of available targeted agents. In addition to the monoclonal antibody, bevacizumab, VEGF receptor tyrosine kinase inhibitors, multitargeted kinase inhibitors, and combination VEGF and epidermal growth factor receptor (EGFR) inhibition, are all being evaluated in NSCLC. Small phase I and II trials have suggested modest benefit when used alone; however, we now know that the anti-angiogenic therapies work best in combination with chemotherapy. The results of ongoing trials using these agents in combination with standard therapy will provide more insight into their potential benefit. As it is known that small tumors require angiogenesis to grow and metastasize, the use of anti-angiogenic therapies in the adjuvant setting may provide even greater benefit, and increase the potential cure rate in this population of patients. The results of well-designed phase III trials will be required to truly understand how to best use this class of targeted therapies in resectable and metastatic NSCLC.
0 Communities
1 Members
0 Resources
6 MeSH Terms
Vascular endothelial growth factor-trap overcomes defects in dendritic cell differentiation but does not improve antigen-specific immune responses.
Fricke I, Mirza N, Dupont J, Lockhart C, Jackson A, Lee JH, Sosman JA, Gabrilovich DI
(2007) Clin Cancer Res 13: 4840-8
MeSH Terms: Adult, Aged, Cell Differentiation, Dendritic Cells, Female, Humans, Immunoglobulin Fc Fragments, Male, Middle Aged, Neoplasms, Receptors, Vascular Endothelial Growth Factor, Recombinant Fusion Proteins, T-Lymphocytes, Regulatory, Vascular Endothelial Growth Factor A
Show Abstract · Added March 20, 2014
PURPOSE - Induction of antitumor immune responses requires adequate function of dendritic cells. Dendritic cell defects in cancer patients have been implicated in tumor escape and the limited efficacy of cancer vaccines. Previous studies have shown that vascular endothelial growth factor (VEGF) plays a major role in abnormal dendritic cell differentiation and function in cancer. It has been proposed that inhibition of VEGF may result in improved immune responses. The goal of this study was to test this hypothesis.
EXPERIMENTAL DESIGN - Fifteen patients with refractory solid tumors were enrolled into a phase I clinical trial of VEGF-Trap. Phenotype and function of different subsets of mononuclear cells were measured before and at different time points after the start of treatment.
RESULTS - VEGF-Trap treatment did not affect the total population of dendritic cells, their myeloid or plasmacytoid subsets, myeloid-derived suppressor cells (MDSC), or regulatory T cells. It significantly increased the proportion of mature dendritic cells. However, that improvement was not associated with an overall increase in immune responses to various antigens and mitogens. A subset analysis revealed significant improvement in immune responses in patients who had no increase in the proportion of MDSC. An improvement in immune responses was absent in patients with an increase in the proportion of MDSC.
CONCLUSIONS - Inhibition of VEGF signaling may improve differentiation of dendritic cells in cancer patients. However, it was not sufficient to improve immune responses. This shows multifaceted nature of immune deficiency and points out to the need for complex approach to modulation of immune reactivity in cancer.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Artery/vein specification is governed by opposing phosphatidylinositol-3 kinase and MAP kinase/ERK signaling.
Hong CC, Peterson QP, Hong JY, Peterson RT
(2006) Curr Biol 16: 1366-72
MeSH Terms: Animals, Arteries, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Embryo, Nonmammalian, Endothelial Cells, Endothelium, Vascular, Extracellular Signal-Regulated MAP Kinases, MAP Kinase Signaling System, Mutation, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor A, Veins, Zebrafish, Zebrafish Proteins
Show Abstract · Added August 19, 2012
Angioblasts are multipotent progenitor cells that give rise to arteries or veins . Genetic disruption of the gridlock gene perturbs the artery/vein balance, resulting in generation of insufficient numbers of arterial cells . However, within angioblasts the precise biochemical signals that determine the artery/vein cell-fate decision are poorly understood. We have identified by chemical screening two classes of compounds that compensate for a mutation in the gridlock gene . Both target the VEGF signaling pathway and reveal two downstream branches emanating from the VEGF receptor with opposing effects on arterial specification. We show that activation of ERK (p42/44 MAP kinase) is a specific marker of early arterial progenitors and is among the earliest known determinants of arterial specification. In embryos, cells fated to contribute to arteries express high levels of activated ERK, whereas cells fated to contribute to veins do not. Inhibiting the phosphatidylinositol-3 kinase (PI3K) branch with GS4898 or known PI3K inhibitors, or by expression of a dominant-negative form of AKT promotes arterial specification. Conversely, inhibition of the ERK branch blocks arterial specification, and expression of constitutively active AKT promotes venous specification. In summary, chemical genetic analysis has uncovered unanticipated opposing roles of PI3K and ERK in artery/vein specification.
1 Communities
1 Members
0 Resources
17 MeSH Terms
Anti-angiogenic treatment of gastrointestinal malignancies.
Salmon JS, Lockhart AC, Berlin J
(2005) Cancer Invest 23: 712-26
MeSH Terms: Angiogenesis Inhibitors, Animals, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Bevacizumab, Colorectal Neoplasms, Humans, Immunotherapy, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor A
Show Abstract · Added March 20, 2014
The scientific rationale to block angiogenesis as a treatment strategy for human cancer has been developed over the last 30 years, but is only now entering the clinical arena. Preclinical studies have demonstrated the importance of the vascular endothelial growth factor (VEGF) pathways in both physiologic and pathologic angiogenesis, and have led to the development of approaches to block its role in tumor angiogenesis. Bevacizumab is an antibody to VEGF and has been shown to prolong survival when given with chemotherapy in the treatment of metastatic colorectal cancer (CRC). Although this is the first anti-angiogenic treatment to be approved for the treatment of human epithelial malignancy, a number of other approaches currently are in development. Soluble chimeric receptors to sequester serum VEGF and monoclonal antibodies against VEGF receptors have both shown considerable promise in the laboratory and are being brought into clinical investigation. A number of small-molecule tyrosine kinase inhibitors that have activity against VEGF receptors also are in clinical trials. Although these novel treatments are being pioneered in CRC, anti-angiogenic approaches also are being tested in the treatment of other gastrointestinal malignancies. Anti-VEGF therapy has shown promise in such traditionally resistant tumors as pancreatic cancer and hepatocellular carcinoma. This review will examine the preclinical foundation and then focus on the clinical studies of anti-VEGF therapy in gastrointestinal cancers.
0 Communities
1 Members
0 Resources
10 MeSH Terms
The vascular endothelial growth factor family and its receptors.
Parikh AA, Ellis LM
(2004) Hematol Oncol Clin North Am 18: 951-71, vii
MeSH Terms: Animals, Endothelium, Vascular, Humans, Neoplasms, Neovascularization, Pathologic, Neovascularization, Physiologic, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor A
Show Abstract · Added March 5, 2014
This article focuses on describing the biology of vascular endothelial growth factor (VEGF) and its receptors as well as the regulation of their expression. A thorough understanding of the VEGF system is paramount in optimizing antiangiogenic therapies as a component of antineoplastic regimens.
0 Communities
1 Members
0 Resources
8 MeSH Terms
Expression and regulation of the novel vascular endothelial growth factor receptor neuropilin-1 by epidermal growth factor in human pancreatic carcinoma.
Parikh AA, Liu WB, Fan F, Stoeltzing O, Reinmuth N, Bruns CJ, Bucana CD, Evans DB, Ellis LM
(2003) Cancer 98: 720-9
MeSH Terms: Adenocarcinoma, Blotting, Northern, Dose-Response Relationship, Drug, Epidermal Growth Factor, Humans, Immunohistochemistry, Keratins, Mitogen-Activated Protein Kinases, Neuropilin-1, Pancreas, Pancreatic Neoplasms, Phosphatidylinositol 3-Kinases, RNA, Messenger, Receptors, Vascular Endothelial Growth Factor, Signal Transduction, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha
Show Abstract · Added March 5, 2014
BACKGROUND - It was recently shown that neuropilin-1 (NRP-1), which was described originally as a receptor for the semaphorins/collapsins (ligands involved in neuronal guidance), is a coreceptor for vascular endothelial growth factor (VEGF) and increases the affinity of specific isoforms of VEGF to its receptor, VEGF-R2.
METHODS - The authors investigated the expression and regulation of NRP-1 in human pancreatic adenocarcinoma specimens and cell lines.
RESULTS - Immunohistochemical analysis revealed that NRP-1 was expressed in 12 of 12 human pancreatic adenocarcinoma specimens but was absent in nonmalignant pancreatic tissue. Northern blot analysis revealed NRP-1 mRNA expression in 8 of 11 human pancreatic adenocarcinoma cell lines. NRP-1 mRNA expression was increased by epidermal growth factor (EGF) but not by tumor necrosis factor alpha in several of the human pancreatic adenocarcinoma cell lines studied. Treating human Panc-48 adenocarcinoma cells with EGF activated Akt and Erk but not P-38. Blockade of the phosphatidylinositol-3 kinase (PI-3K)/Akt, mitogen-activated protein kinase (MAPK)/Erk, or P-38 pathways abrogated EGF-induced NRP-1 expression. Finally, EGF receptor blockade in vivo led to a decrease in NRP-1 expression in an orthotopic model of human pancreatic carcinoma.
CONCLUSIONS - NRP-1 is expressed in most human pancreatic adenocarcinomas and cell lines but not in nonmalignant pancreatic tissue. EGF regulates NRP-1 expression through the PI-3K/Akt and MAPK/Erk signaling pathways, and blockade of the EGF receptor is associated with decreased expression of NRP-1 in vivo. NRP-1 may act as a coreceptor for VEGF in pancreatic carcinoma, as it does in other tumor systems, thereby enhancing angiogenesis and the effect of VEGF on the growth of pancreatic adenocarcinoma.
Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11560
0 Communities
1 Members
0 Resources
17 MeSH Terms
Blockade of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling for therapy of metastatic human pancreatic cancer.
Baker CH, Solorzano CC, Fidler IJ
(2002) Cancer Res 62: 1996-2003
MeSH Terms: Angiogenesis Inhibitors, Animals, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Cell Division, Deoxycytidine, Endothelium, Vascular, ErbB Receptors, Humans, Immunohistochemistry, Male, Mice, Mice, Nude, Neoplasm Metastasis, Neovascularization, Pathologic, Pancreatic Neoplasms, Phthalazines, Pyridines, Pyrimidines, Pyrroles, Receptor Protein-Tyrosine Kinases, Receptors, Growth Factor, Receptors, Vascular Endothelial Growth Factor, Signal Transduction, Xenograft Model Antitumor Assays
Show Abstract · Added March 5, 2014
We determined whether concurrent blockage of vascular endothelial growth factor (VEGF) receptor and epidermal growth factor (EGF) receptor signaling by two novel tyrosine kinase inhibitors, PTK 787 and PKI 166, respectively, can inhibit angiogenesis and, hence, the growth and metastasis of human pancreatic carcinoma in nude mice. Highly metastatic human pancreatic carcinoma L3.6pl cells were injected into the pancreas of nude mice. Seven days later, groups of mice began receiving oral doses of PTK 787 and PKI 166 three times weekly. Some groups of mice also received i.p. injections of gemcitabine twice a week. The mice were necropsied when the control mice became moribund. Treatment with PTK 787 and PKI 166, with gemcitabine alone, or with the combination of PTK 787, PKI 166, and gemcitabine produced 69, 50, and 97% reduction in the volume of pancreatic tumors, respectively. Administration of protein tyrosine kinase inhibitors and gemcitabine also significantly decreased the incidence of lymph node and liver metastasis. The therapeutic efficacy directly correlated with a decrease in circulating proangiogenic molecules (VEGF, interleukin-8), a decrease in microvessel density, a decrease in proliferating cell nuclear antigen staining, and an increase in apoptosis of tumor cells and endothelial cells. Therapies produced by combining gemcitabine with either PKI 166 or PTK 787 were similar to those produced by combining gemcitabine with both PKI 166 and PTK 787. These results suggest that blockade of either epidermal growth factor receptor or VEGF receptor signaling combined with chemotherapy provides an effective approach to the therapy of pancreatic cancer.
0 Communities
1 Members
0 Resources
25 MeSH Terms