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

González-Rodríguez, Beatriz; Heras, Karina Villar Gómez de las; Aguirre, Daniel T; Rodríguez‐Padial, Luis; Albiñana, Virginia; Recio-Poveda, Lucía; Cuesta, Ángel M.; Botella, Luisa M.; Jiménez-Escribano, Rosa María

doi:10.1136/bmjophth-2018-000203

Cited by 15 publications

(21 citation statements)

References 25 publications

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“…The present work demonstrates that the selective β2-adrenergic receptor blocker ICI, has similar effects that Propranolol 20 and in some tests shows improved results. In particular, as shown in results, ICI decreases viability, triggers apoptosis, inhibits hemangiosphere formation, cell migration, and angiogenesis processes, as well as decreases HIF levels and HIF-1 α nuclear translocation.…”

Section: Discussionsupporting

confidence: 67%

“…Basically, Propranolol was acting in two ways: i) decreasing cell viability by triggering apoptosis and ii) inhibiting the expression of HIF-dependent targets in VHL HB cells, where HIF-1α degradation is impaired 21 . Moreover, a phase 3 clinical trial, conducted by the Spanish VHL Alliance, addressed the therapeutical benefits of Propranolol in VHL patients suffering from retina HBs (a different subpopulation of the CNS Hemangioblastomas), Over the time of the trial, retinal tumours did not grow and HB-derived exudates present in 2 different patients, disappeared completely between 3 and 6 months of treatment 19,20 .…”

Section: Discussionmentioning

confidence: 99%

“…Propranolol is prescribed for the treatment of arrhythmia, hypertension, migraines, and other cardiac and neurological diseases, as well as infantile hemangioma [15][16][17][18] . In addition, our lab has demonstrated in vitro and in a clinical trial (EudraCT: 2014-003671-30), the therapeutical properties of Propranolol in VHL disease 19,20 . In brief, Propranolol-treated primary cultured hemangioblastoma (HB) cells decreased the RNA and protein expression levels of HIF-1α and HIF-2α, and therefore the pro-angiogenic and HIF-1α targets such us Endoglin, VEGF, EPO, and SOX.…”

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confidence: 99%

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The β2-adrenergic receptor antagonist ICI-118,551 blocks the constitutively activated HIF signalling in hemangioblastomas from von Hippel-Lindau disease

Cuesta

Albiñana

Gallardo-Vara

et al. 2019

Sci Rep

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One of the major consequences of the lack of a functional VHL protein in von Hippel-Lindau disease, a rare cancer, is the constitutive activation of the HIF pathway. This activation ends up in the generation of Central Nervous System (CNS) Hemangioblastomas among other tumours along the lifespan of the patient. Nowadays, only surgery has been proven efficient as therapy since the systemic attempts have failed. Propranolol, a non-specific β1-and β2-adrenergic receptor antagonist, was recently designated as the first therapeutic (orphan) drug for VHL disease. Nevertheless, its β1 affinity provokes the decrease in blood pressure, being not recommended for low or regular blood pressure VHL patients. In order to overcome the β1-drawback, the properties of a high specific β2-adrenergic receptor blocker named ICI-118,551 have been studied. ICI-118,551 was able to decrease Hemangioblastomas cell viability in a specific manner, by triggering apoptosis. Moreover, ICI-118,551 also impaired the nuclear internalization of HIF-1α in Hemangioblastomas and hypoxic primary endothelial cells, reducing significantly the activation of HIF-target genes and halting the tumour-related angiogenic processes. In this work, we demonstrate the therapeutical properties of ICI-118,551 in VHL-derived CNS-Hemangioblastoma primary cultures, becoming a promising drug for VHL disease and other HIF-related diseases. Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited genetic disorder with an incidence of 1 per 36,000 individuals in the general population and is considered as a rare disease or rare cancer 1,2. Patients with VHL disease harbour a single mutation allele in the tumour suppressor gene VHL (3p25-p26). VHL protein (pVHL) controls the cytoplasmic levels of the Hypoxia Inducible Factor (HIF) complex. In normoxic conditions, pVHL binds to the previously hydroxylated prolyl residues of HIF-1α and HIF-2α, being ubiquitinated and targeted to the proteasome for rapid degradation. When patients suffer a spontaneous inactivation or loss of the second wild-type VHL allele (loss of heterozygosity), either there is no expression of the pVHL or the mutated form is not functional 3,4. Therefore, in the absence of functional pVHL, HIF-1α and HIF-2α subunits accumulate within the cytoplasm and translocate to the nucleus, triggering the hypoxia program by targeting hypoxia responsive genes, which are normally silenced in normoxia 5. HIF-1α and HIF-2α are involved in cell proliferation, angiogenesis, extracellular matrix degradation, vascular tone, and erythropoiesis, among other processes. Hence, cells from VHL tumours have a constitutively active HIF program (a pseudo-hypoxic state) due to the absence of functional pVHL 6,7. As a consequence of this pseudo-hypoxic state, the clinical manifestations of the disease include multiple benign and malignant tumours that appear throughout the lifespan of the patient: retinal hemangioblastoma,

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The β2-adrenergic receptor antagonist ICI-118,551 blocks the constitutively activated HIF signalling in hemangioblastomas from von Hippel-Lindau disease

Cuesta

Albiñana

Gallardo-Vara

et al. 2019

Sci Rep

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“…Intravitreal antiVEGF injections, verteporfin photodynamic therapy and surgery (vitrectomy or excision of the tumour) have also been tried. 1,3,4,6,[12][13][14][15][16][17] There is no clue of systemic non-invasive treatment that has proved beneficial on the course of ocular progression of the disease. 12 Propranolol has also demonstrated its benefits and effects as adjuvant treatment in different kinds of cancers such as breast cancer, melanoma, liver cancer, amongst others.…”

Section: Introductionmentioning

confidence: 99%

“…1,3,4,6,[12][13][14][15][16][17] There is no clue of systemic non-invasive treatment that has proved beneficial on the course of ocular progression of the disease. 12 Propranolol has also demonstrated its benefits and effects as adjuvant treatment in different kinds of cancers such as breast cancer, melanoma, liver cancer, amongst others. [18][19][20][21][22] It is a betablocker drug that has shown a proapoptotic effect by increasing BAX gene expression; antiangiogenic effect by decreasing plasma concentrations of vascular endothelial growth factor (VEGF); and a reduction in erythropoietin (EPO), Sox-2 and Oct-4, all genes involved in angiogenesis and stemness.…”

Section: Introductionmentioning

confidence: 99%

Oral Propranolol in Von Hippel Lindau Ocular Affection

González-Rodríguez

Ramírez

et al. 2020

Preprint

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Background. von Hippel Lindau (VHL) disease is a familial syndrome associated with benign and malignant tumours. These tumours appear in the retina, among other locations. The retinal hemangioblastomas are one of the earliest and most frequent manifestations of this entity, and they can lead to blindness at a young age. Propranolol could be a promising treatment for retinal hemangioblastomas in von Hippel Lindau disease Methods. Prospective cohort study of seven patients with VHL disease and ocular affection that had rejected conventional treatment, taking oral propranolol. We evaluated them for three years, with a complete ophthalmic evaluation that included: visual acuity, intraocular pressure, an examination of the anterior segment of the eye, fundoscopy, retinography, and optical coherence tomography (OCT). Heart rate and blood pressure were also measured. During the follow-up evaluation, two patients discontinued the treatment with propranolol after the first year and rejected any further treatment for their ocular affection; the rest continued therapy. Results. Visual acuity and tumour areas remained stable in 4 patients. Increased and new retinal exudation area was found in the two patients that discontinued the treatment with oral propranolol. Conclusions. Oral propranolol has shown a role in the reabsorption of retinal exudates in patients with VHL affection. It could delay or stabilise the ocular disease, maintaining visual acuity and avoiding further complications in these patients. It is a well-known and available drug, without so many secondary effects, that could also have a role in other ocular diseases that course with exudation. Trial registration. VHL-HOPE-2014-1. EudraCT Number: 2014-003671-30; Registered 22 September 2014 - https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-003671-30/ES

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