Congenital Vascular Lesions, Could MAPK and PI3K Inhibitors Pave the Way to New Therapies?

Abstract

Purpose of Review: Superficial vascular anomalies are a heterogeneous group of malformative and tumoral lesions, developed from various types of abnormal lymphatic and /or blood vessels. They are mostly benign but their clinical evolution can lead to dramatic cosmetic concern, functional impairment and even life-threatening conditions. Until recently, treatments relied on invasive procedures such as embo /sclerotherapy and/ or surgery. Recent molecular findings pave the way of new medical therapies.

Recent Findings: Two main signaling pathways PI3K-AKT-mTOR and RAS-MAPK-ERK are now identified to encounter for the causative pathogenic genetic variants of most vascular anomalies. Involved genes are also responsible for several common neoplasms for which targeted therapies are already available or under development. Repurposing treatment strategy is considered for vascular anomalies treatment with promising results.

Summary: The mTOR inhibitor Sirolimus is the most used targeted therapy so far, but new molecules are tested currently.

Key Points

• The understanding of pathophysiological mechanisms in superficial vascular anomalies has dramatically improved, leading to the identification of causative genes of most vascular conditions.

• The causative genes of vascular anomalies are also implicated in several common neoplasms for which targeted therapy are already available or are in developing process, then repurposing strategy is considered.

• While Sirolimus is the most used targeted therapy with important data supporting its efficacy, other treatments such as alpelisib, and trametinib are tested currently.

Introduction

Congenital vascular malformations regroup a large field of various benign lesions made of different types of vessels. A majority of them are sporadic inborn vasculogenesis errors.

The first classification initiated in 1982 by Mulliken and Glowacki [1] was based on clinical features, natural history, cellular turnover and histology. The vascular tumors characterized by cell hyperplasia were first separated from vascular malformations made of various types of dysplastic vessels. Vascular malformations were subclassified according to flow characteristics (slow or high flow) studied on imaging and subsequently to immunostaining characteristics (GLUT 1 immunostaining and lymphatic markers) [1].

During the last 10 years, genetic research has dramatically improved, leading to the identification of the pathogenic variants of most of the known vascular anomalies, implemented in the last update of the classification in 2018 [2,3]. Those recent insights on the genetic basis of vascular anomalies pave the way to potential new therapies.

Vascular Malformations

Clinical presentations of vascular malformations are variable and represent a large spectrum ranging from asymptomatic birthmarks « angiomas » to large life-threatening conditions. They are present at birth and grow slowly with the patient.

Slow-flow vascular malformations encounter for capillary malformations, lymphatic malformations and venous malformations. High-flow vascular malformations consist of arteriovenous malformations and arteriovenous fistula.

Capillary malformations also named port-wine-stains consist of pink or red macules, present at birth and persistent through life, responsible for cosmetic concern.

Lymphatic malformations consist of dilated lymphatic channels or cysts. They can be microcystic, macrocystic, or mixed and are mostly located in soft tissue. Main symptoms are painful inflammatory flares with bleeding and lymph leakage, as well as cosmetic concern. In rarer multifocal presentations (generalized lymphatic anomaly and Gorham disease) organ involvement, mostly bone, but also spleen and lung may be observed, with more severe symptoms such as bone fractures, pleural effusion.

Venous malformations are usually unifocal soft compressible subcutaneous masses with bluish skin discoloration. Recurrent thrombophlebitis occurring within the enlarged vessels is a typical feature, leading to chronic, sometimes severe pain responsible for functional impairment. They occur mostly sporadically, but few familial forms exist.

Arteriovenous Malformations (AVMs) are much rarer vascular anomalies, composed of malformed arteries, veins, and capillaries. They are present as warm painful pulsating lesions. Complications consist of ulceration, which can lead to severe bleeding and cardiac overload which may be complicated by heart failure, due to arteriovenous shunting.

A range of vascular malformations syndromes composed by a combination of slow and/or high flow lesions and other tissue anomalies, in particular overgrowth, can also be observed.

Genetics

Recent biological and molecular findings with Next Generation Sequencing techniques (NGS) have considerably improved during the last decade in exploring vascular malformations. Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) have been performed in the blood and on affected tissue of patients [4,5]. In most sporadic presentations, a pathogenic variant was identified within the tissue, but not in the blood; the occurrence of such a postzygotic variant is the pathogenic basis of mosaic disorders, that include most of vascular anomalies. Two pathways are now well identified in the pathogenesis of vascular anomalies. The PI3K/AKT/mTOR pathway which is implicated in many cellular processes, such as cellcycle regulation, proliferation, protein synthesis, and cell survival, and the RAS/MAPK/ERK signaling pathway, involved in cell-cycle regulation, cell proliferation, and migration [6]. A high-throughput sequencing study carried out using 319 tissue samples from patients with vascular malformations revealed a somatic variant in one of the players in these pathways in approximately 50% of patients [7].

TEK variants encoding for the TIE2 protein located right upstream the PIK3CA PI3K/AKT/mTOR pathway were first identified in familial and then sporadic forms of VM.

In familial forms of VM a germinal variant in TEK is identified in most of cases but a second somatic “hit” is necessary for the development of lesions. This paradominant model of inheritance was also described for other rare familial forms of vascular malformations like Glomuvenous malformations or syndromic forms like CMAVM1 or recently in vascular malformations of hereditary hemorrhagic telangiectasia patients [8-10].

Since then, many pathogenic somatic variants were identified in PIK3CA in several types of vascular malformations including simple slow-flow Vascular Malformations (VM, LM) and rare subtypes such as Fibroadipose Vascular Anomaly (FAVA), as well as combined vascular anomalies such as Congenital Lipomatous Overgrowth Vascular Epidermal and Squeletal anomaly (CLOVES), Klippel-Trenaunay Syndrome (KTS) or Megalencephaly-Capillary Malformation (MCAP) belonging to the spectrum of PIK3CArelated overgrowth syndrome or in generalized lymphatic anomalies. Variants in other genes of the pathway were also identified like in PTEN hamartoma tumor syndrome and Proteus Syndrome respectively associated to germinal PTEN variants and somatic AKT1 variants. Two others inherited diseases are more indirectly linked to PIK3CA/ AKT/mTOR pathway namely Hereditary hemorrhagic telangiectasia associated to loss-of function mutations in ACVRL1 and ENG and glomuvenous malformations associated to GLMN variants. Indeed, it was shown that ACVRL1 deficiency leads to increased PI3K pathway activation and that pharmacological PI3K inhibition prevents AVM formation in a mouse model deficient for ACVRL1 [11].

Somatic pathogenic variants in genes involved in the RAS/ MAPK/ERK pathway are mainly responsible for arteriovenous malformations. MAP2K1 variants were identified in extracranial AVM and KRAS/BRAF variants were identified in cerebral AVM. The guanine nucleotide-binding protein subunit alpha q (Gaq) is an upstream element of the MAPK pathway composed by several subunits encoded by GNAQ, GNA11, and GNA14 genes. Somatic gain of function mutations in GNAQ were identified in isolated CMs and Sturge-Weber syndrome and GNA11 variants were identified in diffuse CM with overgrowth [12,13]. Interestingly, GNA11 variants were described in congenital hemangioma and GNA14 variants in Kaposiform Hemangioendothelioma (KHE) both high-flow vascular anomalies classified as vascular tumors. Various lymphatic anomalies were also associated to somatic variants leading to the activation of the MAPK pathway since NRAS variants were identified in kaposiform lymphangiomatosis and generalized lymphatic anomalies whereas ARAF variants were identified in patients presenting central conducting lymphatic anomalies [14]. It is of note that a germline EPHB4 mutation was also identified in one CCLA family [15].

Currently Genes related to PIK3CA/AKT/mTOR or RAS/MAPK/ ERK pathways for which mutations have been described in vascular malformations are summarized in Table 1. Most of identified variants activate PI3K or MAPK pathways by sitting on very specific domains of growth factors, or by causing loss of function on growth inhibitor proteins. The discovery of these genetic abnormalities leads to consider the use of therapeutic molecules targeting these signaling pathways according to their molecular profile.

  

    
Pathway
    
Disease
    
Gene
    
Mutation type
  
  

    
Slow-flow vascular malformations
  
  

    
PI3K/AKT/mTOR
    
Multiple cutaneous and mucosal venous
    
TEK
    
G/G+S/S
  
  

    
Sporadic Venous malformations
    
TEK, PIK3CA
    
S
  
  

    
Blue rubber bleb naevus syndrome
    
TEK
    
S
  
  

    
Lymphatic malformations
    
PIK3CA
    
S
  
  

    
Fibro adipose vascular anomalies
    
PIK3CA
    
S
  
  

    
Glomuvenous malformations
    
GLMN
    
G/G+S
  
  

    
RAS/MAPK/ERK
    
Verrucous Venous malformation
    
MAP3K3
    
S
  
  

    
Isolated capillary malformations
    
GNAQ
    
S
  
  

    
High-flow vascular malformations
  
  

    
RAS/MAPK/ERK
    
Extracranial Arteriovenous malformations
    
MAP2K1
    
S
  
  

    
Cerebral arteriovenous malformations
    
KRAS, BRAF
    
S
  
  

    
PI3K/AKT/mTOR
    
Hereditary hemorrhagic telangiectasia
    
ACVRL1, ENG
    
G/G+S
  
  

    
Complex-combined vascular malformations
  
  

    
PI3K/AKT/mTOR
    
Proteus Syndrome
    
AKT1
    
S
  
  

    
PTEN hamartoma tumor syndrome
    
PTEN
    
G/G+S
  
  

    
PIK3CA related overgrowth syndrome
    
PIK3CA
    
S
  
  

    
Generalized lymphatic anomalies
    
PIK3CA
    
S
  
  

    
RAS/MAPK/ERK
    
NRAS
    
S
  
  

    
Kaposiform lymphangiomatosis
    
NRAS
    
S
  
  

    
Central conducting lymphatic anomalies
    
EPHB4/
    
G/S
  
  

    
Sturge-Weber syndrome
    
GNAQ
    
S
  
  

    
Diffuse capillary malformations with overgrowth
    
GNA11
    
S
  
  

    
Capillary malformation-arteriovenous malformation type 1
    
RASA1
    
G/G+S
  
  

    
Capillary malformation-arteriovenous malformation type 2
    
EPHB4
    
G
  
  

    
G:    Germline mutation; G+S: Germline and Somatic second hit; S: Somatic mutation. 
  

Table 1: Genes related to PIK3CA/AKT/mTOR or RAS/MAPK/ERK pathways for which mutations have been described in vascular malformations.