Pazopanib in patients with von Hippel-Lindau disease: a single-arm, single-centre, phase 2 trial

Jonasch, Eric; McCutcheon, Ian E.; Gombos, Dan S.; Ahrar, Kamran; Perrier, Nancy D.; Liu, Diane; Robichaux, Christine; Villarreal, Mercedes F; Weldon, Justin A.; Woodson, Ashley H.; Pilié, Patrick G.; Fuller, Gregory N.; Waguespack, Steven G.; Matin, Surena F.

doi:10.1016/s1470-2045(18)30487-x

Cited by 77 publications

(56 citation statements)

References 29 publications

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“…Thus far, therapeutic options for VHL patients are only derived from surgery and, unfortunately, the preoperative neurological deficits do not resolve after surgery 12 . In addition, the systemic therapies, mainly antiangiogenic, used for metastatic cancers had shown limited response in VHL tumours 13,14 . Therefore, and due to the lack of effective therapies for diffuse or recurrent disease, there is an urgent demand for effective drugs for VHL patients, especially those medicines that might halt the progression of tumours and subsequently delay surgical treatment.…”

mentioning

confidence: 99%

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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confidence: 99%

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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“…Of the 45 patients in whom disease progressed while on first line treatment, 10 (22%) demonstrated response with a disease control rate of 75% [30]. More recently, Jonasch et al demonstrated in a Phase II, single center trial that patients with diagnosed vHL may see response to tumors of multiple organs when started on pazopanib therapy [31]. Of the 31 patients treated with pazopanib, 13 (42%) demonstrated objective response with the most pronounced effect in pancreatic lesions (9 of 17, 53%) and renal cell carcinomas (31 of 59, 52%); only 2 of 49 (4%) CNS hemangioblastomas demonstrated objective response [31].…”

Section: Discussionmentioning

confidence: 99%

“…More recently, Jonasch et al demonstrated in a Phase II, single center trial that patients with diagnosed vHL may see response to tumors of multiple organs when started on pazopanib therapy [31]. Of the 31 patients treated with pazopanib, 13 (42%) demonstrated objective response with the most pronounced effect in pancreatic lesions (9 of 17, 53%) and renal cell carcinomas (31 of 59, 52%); only 2 of 49 (4%) CNS hemangioblastomas demonstrated objective response [31]. These trials illustrate the treatment potential of pazopanib in patients with various tumor types, including those often associated with vHL.…”

Section: Discussionmentioning

confidence: 99%

Clinical response to pazopanib in a patient with endolymphatic sac tumor not associated with von Hippel-Lindau syndrome

Nelson

Bannykh

et al. 2020

CNS Oncol.

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Endolymphatic sac tumors (ELSTs) are rare, locally invasive, vascular tumors of the temporal bone. These lesions are associated with von Hippel-Lindau syndrome but may arise sporadically. Early surgical intervention is recommended to prevent permanent neurologic deficits; however, many ELSTs are unresectable or are subtotally resected due to neurovascular compromise. Chemotherapeutic salvage therapy in trials of neoplasms of associated syndromes has targeted angiogenesis with variable response. We present the case of a sporadic ELST, previously minimally responsive to bevacizumab, treated with pazopanib, a multi-kinase inhibitor and antiangiogenic, with good response. Cases such as our patient may demonstrate the utility of novel antiangiogenics in the treatment of these rare neoplasms, particularly when the tumor is unresectable or necessitates subtotal resection.

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“…An important study published in The Lancet investigated the efficacy of pazopanib in 31 patients with VHL and reported an objective response in 13 patients (42%). However, treatment-related serious adverse events included one case each of appendicitis and gastritis, and one patient had a fatal central nervous system bleeding 21 .…”

Section: Discussionmentioning

confidence: 99%

Applied Precision Cancer Medicine in Neuro-Oncology

Taghizadeh

Müllauer

Furtner

et al. 2019

Sci Rep

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Brain tumours that are refractory to treatment have a poor prognosis and constitute a major challenge in offering effective treatment strategies. By targeting molecular alterations, precision cancer medicine may be a viable option for the treatment of brain tumours. in this retrospective analysis of our PCM platform, we describe the molecular profiling of primary brain tumours from 50 patients. Tumour samples of the patients were examined by a 161-gene next-generation sequencing panel, immunohistochemistry, and fluorescence in situ hybridization (FISH). We identified 103 molecular aberrations in 36 (72%) of the 50 patients. The predominant mutations were TP53 (14.6%), IDH1 (9.7%) and PIK3CA (6.8%). No mutations were detected in 14 (28%) of the 50 patients. IHC demonstrated frequent overexpression of EGFR and mTOR, in 38 (76%) and 35 (70%) patients, respectively. Overexpression of PDGFRa and PDGFRb were less common and detected in 16 and four patients, respectively. For 35 patients a targeted therapy was recommended. In our database, the majority of patients displayed mutations, against which targeted therapy could be offered. Based on our observations, PCM may be a feasible novel treatment approach in neuro-oncology.

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Pazopanib in patients with von Hippel-Lindau disease: a single-arm, single-centre, phase 2 trial

Abstract: Novartis Inc and NIH National Cancer Institute core grant.

Cited by 77 publications

References 29 publications

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

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

Clinical response to pazopanib in a patient with endolymphatic sac tumor not associated with von Hippel-Lindau syndrome

Applied Precision Cancer Medicine in Neuro-Oncology

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