Theranostic Advances in Vascular Malformations

Abstract

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/ mitogen-activated protein kinase and the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin 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.

Frequent activating PIK3CA mutations in sporadic angiolipoma

“…7,31 The proliferative effect of PIK3CA mutations in PROS syndromes exhibits an apparent skewing in the pattern of affected tissues, with mesoderm-derived tissues (including vasculature and adipose tissue) being markedly affected. 32 Importantly, mosaic activating mutations in PIK3CA are also known to cause the majority of isolated lymphatic malformations (>90%) as well as a significant proportion of isolated venous malformations (25%-30%) in the nonsyndromic population 5,6,25 ; unrestrained activation of p110α in endothelial cells leads to a hyperproliferative phenotype and formation of vascular developmental tumors responsive to therapeutic PI3K inhibition. 25 Intermediate PROS phenotypes, characterized by capillary malformations with overgrowth and lipomatous neoformations, are often caused by PIK3CA mutations with intermediate oncogenic potency, including the p.E545A mutation that was detected in our study.…”

“…32 Importantly, mosaic activating mutations in PIK3CA are also known to cause the majority of isolated lymphatic malformations (>90%) as well as a significant proportion of isolated venous malformations (25%-30%) in the nonsyndromic population 5,6,25 ; unrestrained activation of p110α in endothelial cells leads to a hyperproliferative phenotype and formation of vascular developmental tumors responsive to therapeutic PI3K inhibition. 25 Intermediate PROS phenotypes, characterized by capillary malformations with overgrowth and lipomatous neoformations, are often caused by PIK3CA mutations with intermediate oncogenic potency, including the p.E545A mutation that was detected in our study. 31,32 Rare instances of familial angiolipomatosis have been reported, apparently following an autosomal dominant mode of inheritance 9 ;…”

“…The various class I PI3K isoforms show differences in their relative expression levels depending on the cell type; importantly, p110α is the sole isoform required for blood and lymphatic vascular development 25 . The catalytic subunit p110α is frequently mutated in several benign and malignant human neoplasms; cancers with a high prevalence of activating PIK3CA mutations include breast, endometrial, bladder, and colorectal carcinoma 24 .…”

“…The catalytic subunit p110α is frequently mutated in several benign and malignant human neoplasms; cancers with a high prevalence of activating PIK3CA mutations include breast, endometrial, bladder, and colorectal carcinoma 24 . Almost 80% of reported somatically acquired or mosaic PIK3CA mutations map to one of three hot spots in the p110α coding sequence (p.E542K, p.E545K, and p.H1047R) 24‐26 ; however, numerous other rare, cancer‐specific p110α mutations have also been identified 26 . Common features of all PIK3CA oncogenic mutations feature increased lipid kinase activity, constitutive activation of AKT and TOR‐mediated signaling, and sensitivity to rapamycin 22‐24 .…”

Efficacy and safety of sirolimus in the treatment of vascular malformations

“…Further research in the genetic and pathophysiologic origin of VMs demonstrated that VMs caused by abnormal signaling within vascular endothelial cells. [4] The phosphatidylinositol 3-kinase(PI3K)-protein kinase B(AKT)-mammalian target of rapamycin (mTOR) pathway plays a key role in the pathogenesis of VMs. [5] The PI3K/AKT/mTOR pathway is implicated in many cellular processes, such as cell-cycle regulation, proliferation, protein synthesis, and cell survival.…”