Lab related publications

New and Emerging Targeted Therapies for Vascular Malformations

An Van Damme,Emmanuel Seront, Valerie Dekeuleneer, Laurence M. Boon, Miikka Vikkula

Extensive insight into the genetic origin and molecular mechanism of development has been accumulated over the last 20 years. Since the discovery of the first somatic mutations in a vascular anomaly 10 years ago, it is now recognized that they are perhaps all caused by inherited or somatic mutations in genes that hyperactivate two major intracellular signal-ing pathways: the RAS/MAPK/ERK and/or the phosphatidylinositol 3 kinase (PIK3)/protein kinase B/mammalian target of rapamycin (mTOR) pathway. Repurposing of cancer drugs has become a major focus in this rapidly evolving field.

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Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation

Ines Martinez-Corral, Yan Zhang, Milena Petkova, Henrik Ortsäter, Sofie Sjöberg, Sandra D. Castillo, Pascal Brouillard, Louis Libbrecht, Dieter Saur, Mariona Graupera, Kari Alitalo, Laurence Boon, Miikka Vikkula & Taija Mäkinen

Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic). Cellular mechanisms underlying LM pathology are poorly understood. Here we show that the somatic PIK3CAH1047R mutation, resulting in constitutive activation of the p110α PI3K, underlies both macrocystic and microcystic LMs in human.

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Blocking Signalopathic Events to Treat Cerebral Cavernous Malformations

SalimAbdelilah-Seyfried, ElisabethTournier-Lasserve, W. BrentDerry

Cerebral cavernous malformations (CCMs) are caused by the clonal loss of any of three CCM genes within endothelial cells of lowly perfused venous capillary vessel beds. In mouse models of CCM, cavernoma growth is spurred when CCM-deficient clones of vessel-resident endothelial progenitor cells recruit wild-type neighboring endothelial cells. Increasing evidence suggests that nongenetic ‘third hits’ cause an activation of quiescent CCM-deficient cells; this may provide novel avenues for drug treatments directed at blocking acute phases of the CCM pathology.

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Theranostic Advances in Vascular Malformations

V Dekeuleneer, E Seront, A Van Damme, LM Boon, M Vikkula

Until a few years ago, treatment options of vascular malformations were limited to sclerotherapy and/or surgery. Since, it has been demonstrated that the majority of vascular malformations are caused by inherited or somatic mutations in various genes. These discoveries paved the way for the development and testing of targeted molecular inhibitors as therapies for vascular anomalies via repurposing of anticancer drugs.

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A Clinical Feasibility Study to Image Angiogenesis in Patients with Arteriovenous Malformations Using 68Ga-RGD PET/CT

Daphne Lobeek et al.

Arteriovenous malformations (AVMs) have an inherent capacity to form new blood vessels, resulting in excessive lesion growth, and this process is further triggered by the release of angiogenic factors. 68Ga-labeled arginine-glycine-aspartate tripeptide sequence (RGD) PET/CT imaging may provide insight into the angiogenic status and treatment response of AVMs. This clinical feasibility study was performed to demonstrate that 68Ga-RGD PET/CT imaging can be used to quantitatively assess angiogenesis in peripheral AVMs.

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RASA1 mosaic mutations in patients with capillary malformation-arteriovenous malformation

N Revencu, E Fastre , M Ravoet , R Helaers , P Brouillard , A  Bisdorff-Bresson , C Chung , M Gerard , V Dvorakova , A Irvine , L Boon , M Vikkula 

This study shows that RASA1 mosaic mutations can cause capillary malformation-arteriovenous malformation. Thus, highly sensitive sequencing techniques should be considered as diagnostic tools, especially for patients with no family history. Even low-level mosaicism can cause the classical phenotype and increased risk for offspring. In addition, our study further supports the second-hit pathophysiological mechanism to explain the multifocality of vascular lesions in this disorder.

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