semaxinib and von-Hippel-Lindau-Disease

von Hippel-Lindau (VHL) syndrome is a familial cancer syndrome caused by germline mutations in the VHL tumor suppressor gene. Mutations in the VHL gene result in the constitutive stabilization of transcription factors hypoxia-inducible factors 1alpha and 2alpha, which bind to specific enhancer elements in the vascular endothelial growth factor (VEGF) gene and stimulate angiogenesis. This increase in angiogenesis under normoxic conditions in key target organs such as the brain, kidney, and eye leads to high morbidity and reduced life expectancy. Drugs designed to block the VEGF signaling pathway may prevent the long-term complications of the disease. To test this hypothesis, a clinical study was initiated to evaluate the effect of the VEGF tyrosine kinase receptor inhibitor SU5416 in patients with VHL syndrome. Preliminary data on SU5416 indicate that it is well tolerated when administered chronically in such patients. However, since little is known about the long-term use of such inhibitors, patients will need careful monitoring. Data obtained from monitoring these patients will provide valuable information for adjuvant treatment trials in cancer patients.

Topics: Angiogenesis Inhibitors; Endothelial Growth Factors; Enzyme Inhibitors; Genes, Tumor Suppressor; Germ-Line Mutation; Humans; Indoles; Lymphokines; Neovascularization, Pathologic; Protein Isoforms; Protein-Tyrosine Kinases; Pyrroles; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Mitogen; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; von Hippel-Lindau Disease

Topics: Adult; Angiogenesis Inhibitors; Brain Neoplasms; Female; Hemangioblastoma; Humans; Indoles; Male; Middle Aged; Pyrroles; Retinal Neoplasms; Spinal Cord Neoplasms; Treatment Outcome; Vascular Endothelial Growth Factor A; von Hippel-Lindau Disease

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome caused by germline mutations in the VHL tumor-suppressor gene. Central nervous system (CNS) and retinal hemangioblastomas are highly vascular tumors that are hallmarks of the disease. These tumors overexpress vascular endothelial growth factor (VEGF) and represent a potential target for anti-angiogenic drugs. We observed, after 3 to 4 months of treatment, secondary paradoxical polycythemia in 3 VHL patients with CNS or retinal hemangioblastomas treated by the anti-VEGF receptor SU5416. Hematocrit was normal before the beginning of the trial, and no progression of hemangioblastomas was observed. Polycythemia vera and all known causes of secondary polycythemia were also ruled out. Polycythemia has never been reported in current SU5416 trials for advanced malignancies and could express a specific action on red blood cell precursors occurring only in the absence of a functional VHL gene. These findings could also affect the inclusion of VHL patients with pre-existing polycythemia in future anti-VEGF receptor trials.

Topics: Adult; Angiogenesis Inhibitors; Enzyme Inhibitors; Female; Hematocrit; Humans; Indoles; Kinetics; Male; Middle Aged; Polycythemia; Pyrroles; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; von Hippel-Lindau Disease

Topics: Angiogenesis Inhibitors; Biopsy, Needle; Cerebellar Neoplasms; Diagnosis, Differential; Follow-Up Studies; Hemangioblastoma; Humans; Immunohistochemistry; Indoles; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Recurrence, Local; Pyrroles; Risk Assessment; Treatment Outcome; von Hippel-Lindau Disease

To test the efficacy of the novel vascular endothelial growth factor (VEGF) receptor inhibitor SU5416, in a case of refractory von Hippel-Lindau (VHL) retinal hemangioblastoma (RHB).. Interventional case report.. Patient included in a multicenter phase II trial. A 30-year-old woman presenting with VHL disease and multiple RHB on her only eye, refractory to conventional treatments, had decreased visual acuity due to cystoid macular edema (CME). SU5416 was administered intravenously for 7 months. Best-corrected visual acuity (BCVA) and macular thickness were measured by optical coherence tomography.. Under treatment, the size of the RHB did not change, but CME improved significantly. Best-corrected visual acuity rose from 20/40 to 20/25. However, CME recurred after the end of the treatment.. The VEGF receptor inhibitor SU5416 failed to reduce the size of RHB but was very effective for the associated CME.

Topics: Adult; Angiogenesis Inhibitors; Female; Fluorescein Angiography; Hemangioblastoma; Humans; Indoles; Infusions, Intravenous; Macular Edema; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Retinal Neoplasms; Visual Acuity; von Hippel-Lindau Disease

To present a case of rapid and durable recovery of visual function in a patient with von Hippel-Lindau syndrome and optic nerve head hemangioblastoma after systemic treatment with the vascular endothelial growth factor (VEGF) receptor inhibitor SU5416.. Interventional case report.. Visual function parameters, including visual acuity, automated visual field, and contrast sensitivity, were evaluated using standardized methods repeatedly over a 15-month period. Fundus photographs and fluorescein angiograms were also obtained. Central nervous system lesions were monitored by computed tomography (CT) and magnetic resonance imaging (MRI) scans. Treatment involved the systemic administration of the VEGF receptor inhibitor SU5416.. Clinical presentation, visual acuity using Early Treatment Diabetic Retinopathy Study protocol, Humphrey automated perimetry, (Zeiss Humphrey Systems, Dublin, CA) Vistech contrast sensitivity (Vistech Consultants Inc., Dayton, OH) Farnsworth (Farnsworth-Munsell Color Services, New Windsor, NY) dichotomous panel D-15, retinal photography, fluorescein angiography, and CT and MRI scans.. Within 4 weeks of therapy, visual acuity had improved from 20/32(-2) to 20/16(-1), the visual field had expanded from being circumferentially constricted to within 8 degrees of fixation to normal, and contrast sensitivity improved in all but the lowest spatial frequency (1.5 cycles/degree). No change was observed in lesion size by fundus photography. Improvement has been maintained over 18 months with intermittent SU5416 therapy.. We report rapid, extensive, and durable recovery of visual function after systemic administration of the VEGF receptor inhibitor SU5416 to a patient with VHL syndrome and optic nerve head hemangioblastoma. These findings suggest that continued evaluation of VEGF inhibitors for ocular neovascular disorders is warranted.

Topics: Angiogenesis Inhibitors; Contrast Sensitivity; Female; Fluorescein Angiography; Hemangioblastoma; Humans; Indoles; Magnetic Resonance Imaging; Middle Aged; Optic Disk; Optic Nerve Neoplasms; Pyrroles; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Recovery of Function; Visual Acuity; Visual Fields; von Hippel-Lindau Disease