Repurposing propranolol as a drug for the treatment of retinal haemangioblastomas in von Hippel-Lindau disease

Abstract

BackgroundVon Hippel-Lindau (VHL) disease is a rare oncological disease with an incidence of 1:36,000, and is characterized by the growth of different types of tumours. Haemangioblastomas in the central nervous system (CNS) and retina, renal carcinoma and pheochromocytomas are the most common tumours. The absence of treatment for VHL leads to the need of repeated surgeries as the only option for these patients. Targeting VHL-derived tumours with drugs with reduced side effects is urgent to avoid repeated CNS surgeries. Recent reports have demonstrated that propranolol, a β-blocker used for the treatment of hypertension and other cardiac and neurological diseases, is the best option for infantile hemangioma (IH). Propranolol could be an efficient treatment to control haemangioblastoma growth in VHL disease given its antiangiogenic effects that were recently demonstrated by us. The main objective of the present study was the assessment of the efficacy and safety of propranolol on retinal haemangioblastoma in von Hippel-Lindau disease (VHL).Methods7 VHL patients, from different regions of Spain, affected from juxtapapillary or peripheral haemangioblastomas were administered 120 mg propranolol daily. Patients were evaluated every 3 months for 12 months, at Virgen de la Salud Hospital (Toledo). The patients had juxtapapillary or peripheral haemangioblastomas but had refused standard treatments.ResultsPropranolol was initiated with a progressive increase up to a final dose of 120 mg daily. All tumours remained stable, and no new tumours appeared. The reabsorption of retinal exudation was noted in the two patients having exudates. No adverse effects were recorded. VEGF and miRNA 210 levels were monitored in the plasma of patients as possible biomarkers of VHL. These levels decreased in all cases from the first month of treatment.ConclusionsAlthough more studies are necessary, the results of this work suggest that propranolol is a drug to be considered in the treatment of VHL patients with retinal haemangioblastomas. VEGF and miRNA 210 could be used as biomarkers of the VHL disease activity.Trial registrationThe study has a clinical trial design and was registered at EU Clinical Trials Register and Spanish Clinical Studies Registry, EudraCT Number: 2014–003671-30. Registered 2 September 2014.

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

“…In summary, the results of Figs 6 and 7 demonstrate that Propranolol and ICI, both β2-blockers are preventing in some way the translocation of HIF-1α to nuclei which may explain the decrease of gene expression of HIF-targets shown in Fig. 5 and was previously shown in Albiñana et al, 2015/2017 19,21 .…”

“…In this scenario, where surgery and pharmacological therapies show limited recovery and response for CNS VHL disease, an urgent requirement for new and more effective drugs with reduced side effects for these patients are demanded. www.nature.com/scientificreports www.nature.com/scientificreports/ Some previous studies from Shepard et al and our group have demonstrated that Propranolol, a non-specific β1-and β2-blocker, was efficient on in vitro treatment of CNS Hemangioblastomas primary cultures 19,21,52 . 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 .…”

“…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. Moreover, VEGF and miR210 plasma levels from treated patients were reduced after treatment with Propranolol 19,21 .…”

“…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.…”

Repurposing propranolol as an antitumor agent in von Hippel-Lindau disease

“…Plasma VEGF levels have recently been reported to serve as a biomarker in patients with VHL disease taking propranolol for ocular VHL. 1 In a recent study, patients with VHL disease who harbored retinal hemangioblastomas received propranolol up to 120 mg/day. Although no retinal HBs regressed in the study, systemic VEGF levels decreased with prolonged treatment with propranolol, which is consistent with our in vivo findings.…”