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Strategies to overcome therapeutic resistance in renal cell carcinoma.
Siska PJ, Beckermann KE, Rathmell WK, Haake SM
(2017) Urol Oncol 35: 102-110
MeSH Terms: Angiogenesis Inhibitors, Antineoplastic Agents, Carcinoma, Renal Cell, Clinical Trials as Topic, Costimulatory and Inhibitory T-Cell Receptors, Cytotoxicity, Immunologic, Disease Progression, Disease-Free Survival, Drug Resistance, Neoplasm, Humans, Immunotherapy, Kidney, Kidney Neoplasms, Neoplasm Recurrence, Local, Neovascularization, Pathologic, Nephrectomy, Protein Kinase Inhibitors, Receptors, Vascular Endothelial Growth Factor, Signal Transduction, TOR Serine-Threonine Kinases
Show Abstract · Added April 18, 2017
BACKGROUND - Renal cell cancer (RCC) is a prevalent and lethal disease. At time of diagnosis, most patients present with localized disease. For these patients, the standard of care includes nephrectomy with close monitoring thereafter. While many patients will be cured, 5-year recurrence rates range from 30% to 60%. Furthermore, nearly one-third of patients present with metastatic disease at time of diagnosis. Metastatic disease is rarely curable and typically lethal. Cytotoxic chemotherapy and radiation alone are incapable of controlling the disease. Extensive effort was expended in the development of cytokine therapies but response rates remain low. Newer agents targeting angiogenesis and mTOR signaling emerged in the 2000s and revolutionized patient care. While these agents improve progression free survival, the development of resistance is nearly universal. A new era of immunotherapy is now emerging, led by the checkpoint inhibitors. However, therapeutic resistance remains a complex issue that is likely to persist.
METHODS AND PURPOSE - In this review, we systematically evaluate preclinical research and clinical trials that address resistance to the primary RCC therapies, including anti-angiogenesis agents, mTOR inhibitors, and immunotherapies. As clear cell RCC is the most common adult kidney cancer and has been the focus of most studies, it will be the focus of this review.
Copyright © 2017 Elsevier Inc. All rights reserved.
1 Communities
1 Members
0 Resources
20 MeSH Terms
Modulation of VEGF-induced retinal vascular permeability by peroxisome proliferator-activated receptor-β/δ.
Suarez S, McCollum GW, Bretz CA, Yang R, Capozzi ME, Penn JS
(2014) Invest Ophthalmol Vis Sci 55: 8232-40
MeSH Terms: Analysis of Variance, Animals, Capillary Permeability, Cell Membrane, Cells, Cultured, Claudin-1, Claudin-5, Electric Impedance, Endothelial Cells, Extracellular Signal-Regulated MAP Kinases, Humans, Immunohistochemistry, MAP Kinase Signaling System, Mice, Mice, Inbred C57BL, Models, Animal, Peroxisome Proliferator-Activated Receptors, Receptors, Vascular Endothelial Growth Factor, Retina, Retinal Vessels, Sulfones, Thiophenes, Vascular Endothelial Growth Factor A
Show Abstract · Added February 19, 2015
PURPOSE - Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability contributes to diabetic macular edema (DME), a serious vision-threatening condition. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) antagonist/reverse agonist, GSK0660, inhibits VEGF-induced human retinal microvascular endothelial cell (HRMEC) proliferation, tubulogenesis, and oxygen-induced retinal vasculopathy in newborn rats. These VEGF-induced HRMEC behaviors and VEGF-induced disruption of endothelial cell junctional complexes may well share molecular signaling events. Thus, we sought to examine the role of PPARβ/δ in VEGF-induced retinal hyperpermeability.
METHODS - Transendothelial electrical resistance (TEER) measurements were performed on HRMEC monolayers to assess permeability. Claudin-1/Claudin-5 localization in HRMEC monolayers was determined by immunocytochemistry. Extracellular signal-regulated protein kinases 1 and 2 (Erk 1/2) phosphorylation, VEGF receptor 1 (VEGFR1) and R2 were assayed by Western blot analysis. Expression of VEGFR1 and R2 was measured by quantitative RT-PCR. Last, retinal vascular permeability was assayed in vivo by Evans blue extravasation.
RESULTS - Human retinal microvascular endothelial cell monolayers treated with VEGF for 24 hours showed decreased TEER values that were completely reversed by the highest concentration of GSK0660 (10 μM) and PPARβ/δ-directed siRNA (20 μM). In HRMEC treated with VEGF, GSK0660 stabilized tight-junctions as evidenced by Claudin-1 staining, reduced phosphorylation of Erk1/2, and reduced VEGFR1/2 expression. Peroxisome proliferator-activated receptor β/δ siRNA had a similar effect on VEGFR expression and Claudin-1, supporting the specificity of GSK0660 in our experiments. Last, GSK0660 significantly inhibited VEGF-induced retinal vascular permeability and reduced retinal VEGFR1and R2 levels in C57BL/6 mice.
CONCLUSIONS - These data suggest a protective effect for PPARβ/δ antagonism against VEGF-induced vascular permeability, possibly through reduced VEGFR expression. Therefore, antagonism/reverse agonism of PPARβ/δ siRNA may represent a novel therapeutic methodology against retinal hyperpermeability and is worthy of future investigation.
Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
1 Communities
1 Members
0 Resources
23 MeSH Terms
The temporal and spatial development of vascularity in a healing displaced fracture.
Yuasa M, Mignemi NA, Barnett JV, Cates JM, Nyman JS, Okawa A, Yoshii T, Schwartz HS, Stutz CM, Schoenecker JG
(2014) Bone 67: 208-21
MeSH Terms: Angiography, Animals, Femoral Fractures, Fracture Healing, Mice, Microscopy, Fluorescence, Neovascularization, Physiologic, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor A
Show Abstract · Added September 22, 2014
Underlying vascular disease is an important pathophysiologic factor shared among many co-morbid conditions associated with poor fracture healing, such as diabetes, obesity, and age. Determining the temporal and spatial patterns of revascularization following a fracture is essential for devising therapeutic strategies to augment this critical reparative process. Seminal studies conducted in the last century have investigated the pattern of vascularity in bone following a fracture. The consensus model culminating from these classical studies depicts a combination of angiogenesis emanating from both the intact intramedullary and periosteal vasculature. Subsequent to the plethora of experimental fracture angiography in the early to mid-20th century there has been a paucity of reports describing the pattern of revascularization of a healing fracture. Consequently the classical model of revascularization of a displaced fracture has remained largely unchanged. Here, we have overcome the limitations of animal fracture models performed in the above described classical studies by combining novel techniques of bone angiography and a reproducible murine femur fracture model to demonstrate for the first time the complete temporal and spatial pattern of revascularization in a displaced/stabilized fracture. These studies were designed specifically to i) validate the classical model of fracture revascularization of a displaced/stabilized fracture, ii) assess the association between intramedullary and periosteal angiogenesis and iii) elucidate the expression of VEGF/VEGF-R in relation to the classical model. From the studies, in conjunction with classic studies of angiogenesis during fracture repair, we propose a novel model (see abstract graphic) that defines the process of bone revascularization subsequent to injury to guide future approaches to enhance fracture healing. This new model validates and advances the classical model by providing evidence that during the process of revascularization of a displaced fracture 1) periosteal angiogenesis occurs in direct communication with the remaining intact intramedullary vasculature as a result of a vascular shunt and 2) vascular union occurs through an intricate interplay between intramembranous and endochondral VEGF/VEGF-R mediated angiogenesis.
Copyright © 2014 Elsevier Inc. All rights reserved.
1 Communities
6 Members
0 Resources
9 MeSH Terms
Aflibercept--a decoy VEGF receptor.
Ciombor KK, Berlin J
(2014) Curr Oncol Rep 16: 368
MeSH Terms: Angiogenesis Inhibitors, Antineoplastic Agents, Clinical Trials as Topic, Humans, Receptors, Vascular Endothelial Growth Factor, Recombinant Fusion Proteins, Vascular Endothelial Growth Factors
Show Abstract · Added March 20, 2014
Aflibercept (known as ziv-aflibercept in the USA and sold under the trade name Zaltrap®) is a human recombinant fusion protein with antiangiogenic effects that functions as a decoy receptor to bind vascular endothelial growth factors A and B and placental growth factor. Its unique mechanism of action with respect to other agents targeting angiogenesis led investigators to speculate that it may be more ubiquitously efficacious in tumors highly dependent on pathologic angiogenesis for their growth. Despite encouraging preclinical studies in various tumor types, aflibercept has not been proven efficacious in most later-phase clinical studies. In fact, its only currently held US Food and Drug Administration indication is in metastatic colorectal cancer in combination with 5-fluorouracil, leucovorin, and irinotecan for those patients previously treated with an oxaliplatin-containing chemotherapy regimen. Given aflibercept's toxicity profile and cost, further investigation is needed to better understand its mechanism of action and to discover predictive biomarkers for optimization of its appropriate use in treatment of cancer patients.
0 Communities
1 Members
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7 MeSH Terms
Aflibercept.
Ciombor KK, Berlin J, Chan E
(2013) Clin Cancer Res 19: 1920-5
MeSH Terms: Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Colorectal Neoplasms, Disease-Free Survival, Fluorouracil, Humans, Irinotecan, Leucovorin, Neoplasm Metastasis, Organoplatinum Compounds, Oxaliplatin, Placenta Growth Factor, Pregnancy Proteins, Protein Binding, Randomized Controlled Trials as Topic, Receptors, Vascular Endothelial Growth Factor, Recombinant Fusion Proteins, Treatment Outcome, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor B
Show Abstract · Added September 10, 2013
Aflibercept, an intravenously administered anti-VEGF and antiplacental growth factor (PlGF) agent, has recently been approved by the U.S. Food and Drug Administration in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer who have previously received an oxaliplatin-containing chemotherapy regimen. In the phase III VELOUR trial, aflibercept plus FOLFIRI statistically significantly prolonged both progression-free survival (PFS; median PFS for the aflibercept plus FOLFIRI arm was 6.90 vs. 4.67 months for the placebo-plus-FOLFIRI arm) and overall survival (median overall survival for the aflibercept-plus-FOLFIRI arm was 13.50 vs. 12.06 months for the placebo plus FOLFIRI arm), but grade 3 or 4 adverse events were more common with the addition of aflibercept. However, the addition of aflibercept to 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in the phase II AFFIRM trial of first-line treatment of mCRC failed to improve PFS or response rate. As a decoy VEGF receptor, aflibercept (VEGF-Trap) has binding affinity for VEGF-A, VEGF-B, PlGF-1, and PlGF-2, and this is a mechanism of significant interest. Optimal strategies for incorporating aflibercept into treatment regimens that include other anti-VEGF and cytotoxic chemotherapeutic agents, as well as development of predictive biomarkers for treatment response, have yet to be defined.
0 Communities
4 Members
0 Resources
22 MeSH Terms
A phase I trial and pharmacokinetic study of aflibercept (VEGF Trap) in children with refractory solid tumors: a children's oncology group phase I consortium report.
Glade Bender J, Blaney SM, Borinstein S, Reid JM, Baruchel S, Ahern C, Ingle AM, Yamashiro DJ, Chen A, Weigel B, Adamson PC, Park JR
(2012) Clin Cancer Res 18: 5081-9
MeSH Terms: Adolescent, Antineoplastic Agents, Biomarkers, Child, Child, Preschool, Cohort Studies, Female, Humans, Infant, Male, Neoplasms, Receptors, Vascular Endothelial Growth Factor, Recombinant Fusion Proteins, Treatment Outcome, Young Adult
Show Abstract · Added March 31, 2014
PURPOSE - Aflibercept is a novel decoy receptor that efficiently neutralizes circulating VEGF. A pediatric phase I trial was conducted to define the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of aflibercept.
EXPERIMENTAL DESIGN - Cohorts of three to six children with refractory solid tumors received aflibercept intravenously over 60 minutes every 14 days, at 2.0, 2.5, or 3.0 mg/kg/dose. PK sampling and analysis of peripheral blood biomarkers were conducted with the initial dose.
RESULTS - Twenty-one eligible patients were enrolled; 18 were fully evaluable for toxicity. One of six patients receiving 2.0 mg/kg/dose developed dose-limiting intratumoral hemorrhage and two of six receiving 3.0 mg/kg/dose developed either dose-limiting tumor pain or tissue necrosis. None of the six patients receiving 2.5 mg/kg/dose developed DLTs, defining this as the MTD. The most common non-DLTs were hypertension and fatigue. Three patients with hepatocellular carcinoma, hepatoblastoma and clear cell sarcoma had stable disease for >13 weeks. At the MTD, the ratio of free-to-bound aflibercept serum concentration was 2.10 on day 8 but only 0.44 by day 15. A rapid decrease in VEGF (P < 0.05) and increase in placental growth factor (PlGF; P < 0.05) from baseline was observed in response to aflibercept by day 2.
CONCLUSIONS - The aflibercept MTD in children of 2.5 mg/kg/dose every 14 days is lower than the adult recommended dose of 4.0 mg/kg. This dose achieves, but does not sustain, free aflibercept concentrations in excess of bound. Tumor pain and hemorrhage may be evidence of antitumor activity but were dose-limiting.
©2012 AACR.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Screening for germline EGFR T790M mutations through lung cancer genotyping.
Oxnard GR, Miller VA, Robson ME, Azzoli CG, Pao W, Ladanyi M, Arcila ME
(2012) J Thorac Oncol 7: 1049-52
MeSH Terms: Adult, Disease Progression, Female, Genetic Predisposition to Disease, Genetic Testing, Genotype, Germ-Line Mutation, Humans, Incidence, Lung Neoplasms, Male, Middle Aged, Netherlands, Prognosis, Receptors, Vascular Endothelial Growth Factor, Risk Factors, Survival Rate
Show Abstract · Added September 3, 2013
INTRODUCTION - The study of patients carrying germline epidermal [corrected] growth factor receptor (EGFR) mutations, which have been found in cases of familial lung adenocarcinoma, could provide unique insight into lung cancer risk and carcinogenesis in never-smokers. However, investigations into the biology of germline EGFR mutations have been hampered by the lack of an effective strategy for screening for carriers. We hypothesized that patients with lung cancers found to harbor the EGFR T790M resistance mutation before treatment, an uncommon occurrence, would be likely to carry underlying germline T790M mutations.
METHODS - Eleven unrelated patients with lung cancer, harboring an EGFR T790M mutation, were identified from a 7-year institutional experience with tumor genotyping. Ten patients had benign tissue available, which was anonymously tested for the presence of germline EGFR mutations.
RESULTS - Five of 10 cases carried a germline T790M mutation (50%, confidence interval 27%-73%). One patient's cancer exhibited a distinctive indolent growth, which has also been described in preclinical studies of T790M-mutant cancers. A second patient underwent resection of six separate primary lung adenocarcinomas, each carrying different sensitizing EGFR mutations and T790M.
CONCLUSIONS - Genotyping of lung cancers, now commonly performed to predict benefit from treatment with EGFR tyrosine kinase inhibitors, can also be used as a screening tool to identify patients at risk of carrying germline EGFR mutations. Once identified, these patients and their families can be studied prospectively to explore appropriate lung cancer screening strategies. Further studies using existing oncogenomic data to provide insight into underlying germline genetics are warranted.
0 Communities
2 Members
0 Resources
17 MeSH Terms
Relation of vascular growth factors with CT-derived measures of body fat distribution: the Framingham Heart Study.
Kaess BM, Pedley A, Massaro JM, Larson MG, Corsini E, Hoffmann U, Smith HM, Sawyer DB, Vasan RS, Fox CS
(2012) J Clin Endocrinol Metab 97: 987-94
MeSH Terms: Adult, Angiopoietin-2, Body Fat Distribution, Female, Hepatocyte Growth Factor, Humans, Intra-Abdominal Fat, Male, Middle Aged, Obesity, Radiography, Receptor, TIE-2, Receptors, Vascular Endothelial Growth Factor, Risk Factors, Sex Factors, Subcutaneous Fat, Vascular Endothelial Growth Factor A
Show Abstract · Added March 11, 2014
BACKGROUND - Visceral adiposity is associated with metabolic risk. Given that angiogenesis is a key feature of adipogenesis, variation in the association of levels of circulating vascular growth factors (and their soluble receptors) with distinct body fat compartments may explain differences in the systemic pathogenicity of regional fat depots.
METHODS AND RESULTS - Four body fat compartments [visceral adipose tissue (VAT), sc adipose tissue (SAT), thoracic periaortic fat, and pericardial fat] derived from computed tomography were related to serum concentrations of vascular endothelial growth factor (VEGF), the soluble VEGF receptor (fms-like tyrosine kinase-1), hepatocyte growth factor (HGF), and angiopoietin-2 and its soluble receptor (soluble tyrosine kinase with immunoglobulin-like and EGF-like domains 2 sTie-2) in 1806 Framingham Heart Study participants (mean age 44.9 yr, 44.5% women). In multivariable models, we observed positive associations between several fat compartments and VEGF and HGF levels. The magnitude of the associations were similar for VAT, SAT, and periaortic fat. We observed effect modification by sex. A stronger association was observed between VAT and HGF levels in women; higher VAT and periaortic fat were jointly associated with higher HGF concentrations (P=0.02 and P=0.051, respectively). In women within the highest tertile of VAT, HGF levels significantly increased with higher periaortic fat (P=0.0005).
CONCLUSIONS - In our large community-based sample, greater adiposity was associated with higher circulating growth factor levels in general. Additional studies are warranted to confirm the stronger association of VAT and periaortic fat with HGF in women and to examine its potential contribution to the sex-related differences in cardiometabolic risk.
1 Communities
2 Members
0 Resources
17 MeSH Terms
A phase I study of subcutaneously administered aflibercept (VEGF trap) in a new formulation in patients with advanced solid tumors.
Wang-Gillam A, Tew WP, Rothenberg ML, Dupont J, Cooper W, Sternas L, Buzenet G, Sosman JA, Spriggs DR, Lockhart AC
(2012) Invest New Drugs 30: 1958-61
MeSH Terms: Adult, Aged, Angiogenesis Inhibitors, Antineoplastic Agents, Chemistry, Pharmaceutical, Cohort Studies, Female, Humans, Male, Middle Aged, Neoplasms, Neovascularization, Pathologic, Receptors, Vascular Endothelial Growth Factor, Recombinant Fusion Proteins, Vascular Endothelial Growth Factor A
Show Abstract · Added March 20, 2014
Targeting angiogenesis is a valid anti-cancer strategy. Aflibercept is designed to sequester circulating vascular endothelial growth factor (VEGF) by preventing VEGF from binding to its receptors. This phase I study was to evaluate a new formulation of subcutaneously administered aflibercept in patients with advanced solid tumors. Here we report our experience with the toxicity, pharmacokinetic profile and efficacy of the new 100 mg/mL subcutaneous (SC) formulation of aflibercept administered at a dose of at 4 mg/kg every 2 weeks.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Antiangiogenic therapies in early-stage breast cancer.
Derleth C, Mayer IA
(2010) Clin Breast Cancer 10 Suppl 1: E23-31
MeSH Terms: Angiogenesis Inhibitors, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Breast Neoplasms, Chemotherapy, Adjuvant, Female, Humans, Neoadjuvant Therapy, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor A
Show Abstract · Added March 23, 2014
Angiogenesis, which is crucial for the growth and spread of cancer cells, has become an important target for antineoplastic therapies in a variety of malignant tumors. Vascular endothelial growth factor and its receptor promote formation of new blood vessels in tumors. Several drugs, most notably the monoclonal antibody bevacizumab, have been developed to inhibit this process. Clinical trials utilizing bevacizumab and other antiangiogenic drugs in metastatic breast cancer have demonstrated enhanced response rates and prolonged progression-free survival, though no overall survival benefit has been seen. Trials are now under way exploring the use of antiangiogenic agents in patients with early stage breast cancer. We performed a comprehensive review of the published literature (English language), US National Institutes of Health clinical trials registry (ClinicalTrials.gov), and established cooperative groups that revealed approximately 75 clinical trials, completed or ongoing, utilizing antiangiogenic drugs in early-stage breast cancer. A number of phase II trials in the neoadjuvant setting have reported preliminary results suggesting response rates similar to those seen with traditional anthracycline-plus-taxane combination regimens. Most of these early trials have not yet met any survival endpoints. Studies are also ongoing in the adjuvant setting, and these have not yet been reported. The toxicities associated with these agents are similar to those that have been reported in the metastatic trials. Most of these side effects are grade 1 or 2 and are easily manageable; however, there remain a small percentage of patients who sustain life-threatening vascular events, bleeding, or wound-healing complications. This number is significantly higher in patients receiving antiangiogenic drugs when compared with controls. While we eagerly await completion and results of this impressive portfolio of studies in early breast cancer with antiangiogenic agents, there is an urgent need for a more rational patient/antiangiogenic therapy selection with greater insight into predictive factors for toxicities, therapy efficacy, and clinical benefit.
0 Communities
1 Members
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12 MeSH Terms