Neurological applications of belzutifan in von Hippel-Lindau disease

Abstract

Von Hippel Lindau (VHL) disease is a tumor predisposition syndrome caused by mutations in the VHL gene that presents with visceral neoplasms and growths, including clear cell renal cell carcinoma, and central nervous system manifestations, such as hemangioblastomas of the brain and spine. The pathophysiology involves a dysregulation of oxygen sensing caused by inability to degrade HIFα, leading to overactivation of hypoxic pathways. Hemangioblastomas are the most common tumors in patients with VHL and cause significant morbidity. Until recently, there were no systemic therapies available for patients that could effectively reduce the size of these lesions. Belzutifan, the first approved HIF-2α inhibitor, has demonstrated benefit in VHL-associated tumors, with a 30% response rate in hemangioblastomas and ~30-50% reduction in their sizes over the course of treatment. Anemia is the most prominent adverse effect, affecting 76-90% of participants and sometimes requiring dose reduction or transfusion. Other significant adverse events include hypoxia and fatigue. Overall, belzutifan is well tolerated; however, long term data on dosing regimens, safety, and fertility are not yet available. Belzutifan holds promise for treatment of neurological manifestations of VHL and its utility may influence the clinical management paradigms for this patient population.

Discovery of Cycloalkyl[c]thiophenes as Novel Scaffolds for Hypoxia-Inducible Factor-2α Inhibitors

“…The optimization efforts yielded alkyloxy-substituted cyclopenta­[ c ]­thiophenes with exquisite activity in cellular assays, which are the first examples of HIF-2α inhibitors devoid of two linked aromatic rings, a structural motif that was considered obligatory for potent inhibition of HIF-2α to date. Diversifying the available chemotypes for HIF-2α inhibitors is desirable, as it was reported that prolonged treatment with aryloxy-2,3-dihydro-1 H -inden-1-ol derivatives resulted in the acquisition of resistance in patients with ccRCC. − Crystallographic data confirmed that this new chemotype is able to present key pharmacophoric elements in the hydrophobic cavity in such a way that perturbation of key amino acids is appropriately induced. The optimization efforts resulted in the discovery of compound 35r , which exhibited a significant target modulation in tumors in vivo in mice.…”

Predictors of Progression in a Series of 81 Adult Patients Surgically Managed for an Intracranial Hemangioblastoma: Implications for the Postoperative Follow-Up

“…Anemia is the most common adverse effect. Although long-term results are not known, these treatments represent an interesting option [42,46,47].…”

A case report of cerebellar hemangioblastoma simulated brain metastasis shown by magnetic resonance imaging

“…[ 11 , 12 ] The surgical efficacy of sporadic and cystic hemangioblastoma is relatively satisfactory, while the treatment of solid, familial, and multiple HB is still difficult, especially when located in the brainstem and spinal cord. [ 13 ]…”

“…[11,12] The surgical efficacy of sporadic and cystic hemangioblastoma is relatively satisfactory, while the treatment of solid, familial, and multiple HB is still difficult, especially when located in the brainstem and spinal cord. [13] If there is edema around hemangioblastoma, it is easy to be misdiagnosed as brain metastasis on MRI. Recently, a case of cerebellar hemangioblastoma simulated brain metastasis shown by magnetic resonance imaging was admitted to our hospital, which is reported as follows.…”