scholarly journals Evaluation of the safety and effectiveness of oral propranolol in patients with von Hippel-Lindau disease and retinal hemangioblastomas: phase III clinical trial

2019 ◽  
Vol 4 (1) ◽  
pp. e000203 ◽  
Author(s):  
Beatriz González-Rodríguez ◽  
Karina Villar Gómez de las Heras ◽  
Daniel T Aguirre ◽  
Luis Rodríguez-Padial ◽  
Virginia Albiñana ◽  
...  
Keyword(s):  
Disease Activity ◽  
Phase Iii ◽  
Vascular Endothelial ◽  
Cancer Syndrome ◽  
Von Hippel Lindau ◽  
Long Term Effect ◽  
Registration Number ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease ◽  
Endothelial Growth Factor

Backgroundvon Hippel-Lindau disease (VHL) is a multisystem cancer syndrome caused by mutations in the VHL gene. Retinal hemangioblastoma is one of the most common tumours, and when it appears near the optic nerve, its treatment is challenging and risky. To date, no treatment has proven effective in changing the course of the disease. This study was designed to evaluate the safety and effectiveness of propranolol in controlling these tumours.MethodsSeven patients were included. All patients took a daily dose of 120 mg of propranolol for 1 year. Clinical variables were assessed at baseline, and at 1, 3, 6, 9 and 12 months. The primary endpoint of the study was the number and size of retinal hemangioblastomas. On every visit, retinal outcomes and blood biomarkers (such as vascular endothelial growth factor (VEGF) and miR210) were analysed.ResultsNumber and size of retinal hemangioblastomas remained stable in all patients. All of them had initially increased levels of VEGF and miR210. There was a gradual reabsorption of retinal exudation in two patients, correlating with a progressive decrease of both biomarkers. The only adverse effect reported was hypotension in one patient.ConclusionsPropranolol could be used to treat retinal hemangioblastomas in VHL patients, although more studies are needed to determine the ideal dose and long-term effect. VEGF and miR210 should be explored as biomarkers of disease activity. As far as we know, these are the first biomarkers proposed to monitor the VHL disease activity.Trial registration number2014-003671-30

scholarly journals Inactivation of the Arylhydrocarbon Receptor Nuclear Translocator (Arnt) Suppresses von Hippel-Lindau Disease-Associated Vascular Tumors in Mice

2005 ◽  
Vol 25 (8) ◽  
pp. 3163-3172 ◽  
Author(s):  
Erinn B. Rankin ◽  
Debra F. Higgins ◽  
Jacqueline A. Walisser ◽  
Randall S. Johnson ◽  
Christopher A. Bradfield ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Germ Line ◽  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Vascular Tumors ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Arylhydrocarbon Receptor ◽  
Vhl Disease ◽  
Endothelial Growth Factor

ABSTRACT Patients with germ line mutations in the VHL tumor suppressor gene are predisposed to the development of highly vascularized tumors within multiple tissues. Loss of pVHL results in constitutive activation of the transcription factors HIF-1 and HIF-2, whose relative contributions to the pathogenesis of the VHL phenotype have yet to be defined. In order to examine the role of HIF in von Hippel-Lindau (VHL)-associated vascular tumorigenesis, we utilized Cre-loxP-mediated recombination to inactivate hypoxia-inducible factor-1α (Hif-1α) and arylhydrocarbon receptor nuclear translocator (Arnt) genes in a VHL mouse model of cavernous liver hemangiomas and polycythemia. Deletion of Hif-1α did not affect the development of vascular tumors and polycythemia, nor did it suppress the increased expression of vascular endothelial growth factor (Vegf) and erythropoietin (Epo). In contrast, phosphoglycerokinase (Pgk) expression was substantially decreased, providing evidence for target gene-dependent functional redundancy between different Hif transcription factors. Inactivation of Arnt completely suppressed the development of hemangiomas, polycythemia, and Hif-induced gene expression. Here, we demonstrate genetically that the development of VHL-associated vascular tumors in the liver depends on functional ARNT. Furthermore, we provide evidence that individual HIF transcription factors may play distinct roles in the development of specific VHL disease manifestations.

scholarly journals The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity.

1997 ◽  
Vol 17 (9) ◽  
pp. 5629-5639 ◽  
Author(s):  
D Mukhopadhyay ◽  
B Knebelmann ◽  
H T Cohen ◽  
S Ananth ◽  
V P Sukhatme
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Cell Lines ◽  
Promoter Activity ◽  
Suppressor Gene ◽  
Vascular Endothelial ◽  
Vegf Mrna ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Endothelial Growth Factor

The von Hippel-Lindau tumor suppressor gene (VHL) has a critical role in the pathogenesis of clear-cell renal cell carcinoma (RCC), as VHL mutations have been found in both von Hippel-Lindau disease-associated and sporadic RCCs. Recent studies suggest that vascular endothelial growth factor (VEGF) mRNA is upregulated in RCC- and von Hippel-Lindau disease-associated tumors. We have therefore assessed the effect of the VHL gene product on VEGF expression. VEGF promoter-luciferase constructs were transiently cotransfected with a wild-type VHL (wt-VHL) vector in several cell lines, including 293 embryonic kidney and RCC cell lines. wt-VHL protein inhibited VEGF promoter activity in a dose-dependent manner up to 5- to 10-fold. Deletion analysis defined a 144-bp region of the VEGF promoter necessary for VHL repression. This VHL-responsive element is GC rich and specifically binds the transcription factor Sp1 in crude nuclear extracts. In Drosophila cells, cotransfected VHL represses Sp1-mediated activation but not basal activity of the VEGF promoter. We next demonstrated in coimmunoprecipitates that VHL and Sp1 were part of the same complex and, by using a glutathione-S-transferase-VHL fusion protein and purified Sp1, that VHL and Sp1 directly interact. Furthermore, endogenous VEGF mRNA levels were suppressed in permanent RCC cell lines expressing wt-VHL, and nuclear run-on studies indicated that VHL regulation of VEGF occurs at least partly at the transcriptional level. These observations support a new mechanism for VHL-mediated transcriptional repression via a direct inhibitory action on Sp1 and suggest that loss of Sp1 inhibition may be important in the pathogenesis of von Hippel-Lindau disease and RCC.

Continuous angiogenesis inhibition in the treatment for von Hippel–Lindau-related hemangioblastomas of retina and spinal cord

2019 ◽  
Vol 25 (8) ◽  
pp. 2049-2051 ◽  
Author(s):  
Derya Kıvrak Salim
Keyword(s):  
Spinal Cord ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Therapeutic Option ◽  
Suppressor Gene ◽  
Vascular Endothelial ◽  
Pediatric Age ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Endothelial Growth Factor

Hemangioblastomas of central nervous system are rare and indolent. Twenty-five percent of cases are in association with von Hippel–Lindau disease. Surgery is the standard therapy but un-resectable or recurrent cases need radiation or systemic therapy. Defective von Hippel–Lindau tumor suppressor gene leads to vascular endothelial growth factor overexpression and enhance angiogenesis. Here we report a 19-year-old male, diagnosed at pediatric age, who had retinal and spinal cord hemangioblastomas. He was treated 34 months with bevacizumab, afterwards 12 months with thalidomide and tertiary therapy with pazopanib for 9 months which still goes on. In case of need, radiation and surgical procedures were performed. Vascular endothelial growth factor inhibition continuity is a good therapeutic option, which improves outcomes of von Hippel–Lindau-related hemangioblastomas.

scholarly journals Elevated ocular levels of vascular endothelial growth factor in patients with von Hippel-Lindau disease

1997 ◽  
Vol 8 (10) ◽  
pp. 1015-1022 ◽  
Author(s):  
M. Los ◽  
C.J.M. Aarsman ◽  
L. Terpstra ◽  
D. Wittebol-Post ◽  
C.J.M. Lips ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Endothelial Growth Factor

INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY WITH PEGAPTANIB FOR ADVANCED VON HIPPEL-LINDAU DISEASE OF THE RETINA

Retina ◽  
2007 ◽  
Vol 27 (2) ◽  
pp. 150-158 ◽  
Author(s):  
SAM S. DAHR ◽  
MICHAEL CUSICK ◽  
HANNA RODRIGUEZ-COLEMAN ◽  
SUNIL K. SRIVASTAVA ◽  
DARBY J. THOMPSON ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Factor Therapy ◽  
Growth Factor Therapy ◽  
Endothelial Growth Factor

Changes in neovascular activity following fixed dosing with an anti-vascular endothelial growth factor agent over 52 weeks in the phase III VIEW 1 and VIEW 2 studies

2019 ◽  
pp. bjophthalmol-2019-315021
Author(s):  
Darius M Moshfeghi ◽  
Desmond Thompson ◽  
Namrata Saroj
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Disease Activity ◽  
Phase Iii ◽  
Vascular Endothelial ◽  
Post Hoc Analysis ◽  
Fluid Status ◽  
Anti Vegf ◽  
Post Hoc ◽  
Endothelial Growth Factor

Background/aimsTo understand changes in disease activity as assessed by leakage and retinal fluid status in patients with neovascular age-related macular degeneration (nAMD) receiving fixed dosing with an anti-vascular endothelial growth factor (anti-VEGF) agent.MethodsIn the phase III VIEW 1 (NCT00509795) and VIEW 2 (NCT00637377) studies, eyes with nAMD were treated with intravitreal aflibercept or ranibizumab. Independent, masked reading centres determined the presence/absence of leakage (fluorescein angiography) and retinal fluid (optical coherence tomography) at baseline, week 24 and week 52. In this integrated, post hoc analysis of the VIEW studies, the relationship between leakage/fluid status and best-corrected visual acuity (BCVA) was assessed. The impact of baseline lesion type (predominantly classic (PC), minimally classic (MC), occult) was also evaluated. Data from all treatment groups were pooled.Results2373 eyes were included in this analysis. At baseline, 95.4% of eyes presented with both leakage and fluid. By week 52, leakage and fluid were present in 16.0% of eyes. Mean BCVA gains at week 52 were numerically greater in eyes without leakage and fluid versus eyes with both leakage and fluid (10.3 vs 9.2 letters). At week 52, 11.6%, 15.3% and 20.1% of eyes with PC, MC and occult lesions, respectively, had both leakage and fluid present.ConclusionIn this post hoc analysis, fixed dosing with an anti-VEGF agent over 52 weeks eliminated disease activity (absence of both leakage and fluid) in most eyes. The effect of anti-VEGF treatment on leakage/fluid status favoured PC versus occult lesions.

scholarly journals Use of the Tyrosine Kinase Inhibitor Sunitinib in a Patient with von Hippel-Lindau Disease: Targeting Angiogenic Factors in Pheochromocytoma and Other von Hippel-Lindau Disease-Related Tumors

2009 ◽  
Vol 94 (2) ◽  
pp. 386-391 ◽  
Author(s):  
Camilo Jimenez ◽  
Maria E. Cabanillas ◽  
Libero Santarpia ◽  
Eric Jonasch ◽  
Karen L. Kyle ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Performance Status ◽  
Malignant Pheochromocytoma ◽  
Platelet Derived Growth Factor ◽  
Vascular Endothelial ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Endothelial Growth Factor

Abstract Context: von Hippel-Lindau disease is characterized by highly vascularized tumors of multiple organs. Evidence Acquisition: We present a patient with von Hippel-Lindau disease with multiple renal and pancreatic tumors and a malignant pheochromocytoma infiltrative of the sacrum and associated with lymph nodule metastases. The pheochromocytoma expressed high protein level of vascular endothelial growth factor and platelet-derived growth factor-β receptor. The patient presented with a poor performance status, severe pelvic pain, weight loss, and manifestations of catecholamine excess. Evidence Synthesis: Treatment against malignant pheochromocytoma with surgery, chemotherapy, or participation in clinical trials was not feasible because of the patient’s poor performance status, the presence of multiple tumors, and the extension of the pheochromocytoma into the bones. Patient was treated with sunitinib, a potent tyrosine kinase inhibitor of vascular endothelial growth factor, platelet-derived growth factor, RET, c-KIT, and FLT-3 receptors. Six months of treatment with sunitinib was associated with normalization of the patient’s performance status and blood pressure, absence of symptoms of catecholamine excess, weight gain, disappearance of pain, shrinkage of each of the tumors (50% in the largest renal tumor, 38% in the largest islet cell tumor, 21% in the pelvic malignant pheochromocytoma), and reduction of plasma normetanephrines and chromogranin A. Conclusion: This study provides evidence that targeting tyrosine kinase receptors such as the vascular endothelial growth factor pathway and the platelet-derived growth factor-β receptor may have value in the treatment of VHL-related tumors including pheochromocytoma.

Fortgeschrittenes medulläres Schilddrüsenkarzinom: Vandetanib verbessert das progressionsfreie Überleben

2012 ◽  
Vol 03 (02) ◽  
pp. 93-92
Author(s):  
Alexander Kretzschmar
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Phase Iii ◽  
Vascular Endothelial ◽  
Medulläres Schilddrüsenkarzinom ◽  
Epidermal Growth ◽  
Endothelial Growth Factor

Vandetanib ist ein oraler Hemmer des RET-Kinase-, VEGF (Vascular Endothelial Growth Factor Receptor)- und EGFR (Epidermal Growth Factor Receptor)-Signalwegs. In einer zulassungsrelevanten, randomisierten, doppelblinden, placebokontrollierten Phase- III-Studie verlängerte der Tyrosinkinasehemmer das progressionsfreie Überleben (PFS) signifikant länger als Placebo.

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