Dekeuleneer Valérie (1), Seront Emmanuel (1,2), Van Damme An (1,3), Boon Laurence M (1,4) and Vikkula Miikka (1,4,5)
- Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques universitaires Saint-Luc; VASCERN VASCA European Reference Centre
- Institut Roi Albert II, Department of Medical Oncology, Cliniques universitaires Saint-Luc
- Institut Roi Albert II, Department of Pediatric Hematology and Oncology, Cliniques universitaires Saint Luc
- Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium
- WELBIO (Walloon Excellence in Lifesciences and Biotechnology), de Duve Institute, University of Louvain, Brussels, Belgium
Vascular malformations are subdivided into capillary, lymphatic, venous, arteriovenous and mixed malformations, according to the type of affected vessels. Until a few years ago, treatment options 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 mutations lead to hyperactivity of two major signaling pathways: the RAS/MAPK and the PI3K/AKT/mTOR pathways. These discoveries paved the way for the development and testing of targeted molecular inhibitors as therapies for vascular anomalies via repurposing of anticancer drugs.
In this presentation, we will discuss about some genetics advances which permitted to try new targeted drugs for the treatment of severe vascular malformations.
Bibliography
Adams DM, Trenor CC 3rd, Hammill AM, Vinks AA, Patel MN, Chaudry G et al. Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies. Pediatrics 2016;137(2):1-10.
Al-Olabi L, Polubothu S, Dowsett K, Andrews KA, Stadnik P, Joseph AP, et al. Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. J Clin Invest. 2018; 128(11):5185.
Boscolo E, Limaye N, Huang L, Kang KT, Soblet J, Uebelhoer M, et al. Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects. J Clin Invest 2015; 125:3491–504.
Castel P, Carmona FJ, Grego-Bessa J, Berger MF, Viale A, Anderson KV et al. Somatic PIK3CA mutations as a driver of sporadic venous malformations. Sci Transl Med 2016 Mar 30; 8(332):332ra42.
Castillo SD, Tzouanacou E, Zaw-Thin M, Berenjeno IM, Parker VE, Chivite I et al. Somatic activating mutations in PIK3CA cause sporadic venous malformations in mice and humans. Sci Transl Med 2016; 8: 332ra43.
Dekeuleneer V, Seront E, Van Damme A, Boon LM, Vikkula M. Theranostic advances en vascular malformations. J Invest Dermatol. 2020; epub ahead of print.
di Blasio L, Puliafito A, Gagliardi PA, Comunanza V, Somale D, Chiaverina G et al. PI3K/mTOR inhibition promotes the regression of experimental vascular malformations driven by PIK3CA-activating mutations. Cell Death Dis 2018; 9: 45.
Hammer J, Seront E, Duez S, Dupont S, Van Damme A, Schmitz S, et al. Sirolimus is efficacious in treatment for extensive and/or complex slow-flow vascular malformations: a monocentric prospective phase II study. Orphanet J Rare Dis 2018; 13(1):191.
Hammill AM, Wentzel M, Gupta A, Nelson S, Lucky A, Elluru R et al. Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer 2011; 57(6):1018-1024.
Keppler-Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ, Sapp JC, et al. PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria,
differential diagnosis, and evaluation. Am J Med Genet Part A. 2015; 167A(2): 287–95.
Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, Darling TN, Burton-Akright J, Bagheri M et al. Pharmacodynamic study of miransertib in individuals with Proteus syndrome. Am J Hum Genet 2019; 104(3) : 484-491.
Lackner H, Karastaneva A, Schwinger W, Benesch M, Sovinz P, Seidel M, et al. Sirolimus for the treatment of children with various complicated vascular anomalies. Eur J Pediatr. 2015; 174(12):1579–84.
Lekwuttikarn R, Lim YH, Admani S, Choate KA, Teng JMC. Genotype-guided medical treatment of an arteriovenous malformation in a child. JAMA Dermatol 2019; 155:256-257.
Li D. Mutations in genes involved in MAPK pathway cause lymphatic anomalies. Eur Hum Genet Conference, 15-18 June, 2019 Gothenburg, Sweden. Abstract P05.19C.
Lim YH , Douglas SR, Ko CJ, Antaya RJ, McNiff JM, Zhou J, et al. Somatic Activating RAS Mutations Cause Vascular Tumors Including Pyogenic Granuloma. J Invest Dermatol 2015; 135(6): 1698-1700.
Limaye N, Wouters V, Uebelhoer M, Tuominen M, Wirkkala R, Mulliken JB et al. Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nat Genet 2009; 41(01): 118–124.
Limaye N, Kangas J, Mendola A, Godfraind C, Schlögel MJ, Helaers R et al. Somatic activating PIK3CA mutations cause venous malformation. Am J Hum Genet 2015; 97(6):914–21.
Luks VL, Kamitaki N, Vivero MP, Uller W, Rab R, Bovée JV et al. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr 2015; 166(4):1048-54 e1-e5.
Manevitz-Mendelson E, Leichner GS, Barel O, Davidi-Avrahami I, Ziv-Strasser L, Eyal E et al. Somatic NRAS mutation in patient with generalized lymphatic anomaly. Angiogenesis 2018; 21(2):287-298.
Maruani A, Boccara O, Bessis D, Guibaud L, Vabres P, Mazereeuw-Hautier J et al. Treatment of voluminous and complicated superficial slow-flow vascular malformations with sirolimus (PERFORMUS): protocol for a multicenter phase 2 trial with a randomized observational-phase design. Trials 2018 Jun 27; 19(1):340.
Nguyen HL, Boon LM and Vikkula M. Vascular anomalies caused by abnormal signaling within endothelial cells: targets for novel therapies. Sem Intervent Radiol 2017; 34 (3): 233–238.
Nikolaev SI, Vetiska S, Bonilla X, et al. Somatic activating KRAS mutations in arteriovenous malformations of the brain. N Engl J Med. 2018; 378(3):250-261.
Ozeki M, Asada R, Saito AM, Hashimoto H, Fujimura T, Kuroda T, et al. Efficacy and safety of sirolimus treatment for intractable lymphatic anomalies: a study protocol for an open-label, single-arm, multicenter, prospective study (SILA). Regen Ther. 2019; 10: 84-91.
Parker VER, Keppler-Noreuil KM, Faivre L, Luu M, Oden NL, De Silva L et al. Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum. Genet Med 2019; 21(5): 1189-1198.
Queisser A, Boon LM, Vikkula M. Etiology and genetics of congenital vascular lesions. Otolaryngol Clin North Am. 2018 Feb; 51(1): 41-53.
Ricci KW, Hammill AM, Mobberley-Schuman P, Nelson SC, Blatt J, Bender JLG et al. Efficacy of systemic sirolimus in the treatment of generalized lymphatic anomaly and Gorham-Stout disease. Pediatr Blood Cancer. 2019; 66(5):e27614.
Rodriguez-Laguna L, Agra A, Ibanez K, Oliva-Molina G, Gordo G, Khurana N et al. Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly. J Exp Med 2019; 4: 407-418.
Schlögel M, Brouillard P, Boon LM, Vikkula M. Molecular genetics of lymphatic and complex vascular malformations. In: Lymphedema: A concise compendium of theory and practice. Section X: chapter 60. Eds: Byung-Boong Lee and Stanley G. Rockson, 2nd edition, Springer 2018.
Seront E, Van Damme A, Boon LM, Vikkula M. Rapamycin and treatment of venous malformations.Curr Opin Hematol. 2019; 26(3):185-192.
Triana P, Dore M, Cerezo VN, Cervantes M, Sánchez AV, Ferrero MM et al. Sirolimus in the treatment of vascular anomalies. Eur J Pediatr Surg. 2017; 27(1): 86-90.
Triana P, Miguel M, Díaz M, Cabrera M, López Gutiérrez JC. Oral sirolimus: an option in the management of neonates with life-threatening upper airway lymphatic malformations. Lymphat Res Biol. 2019; 17(5): 504-511.
Venot Q, Blanc T, Rabia SH, Berteloot L, Ladraa S, Duong JP et al. Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature. 2018 ;558(7711):540-546.