Orphanet Journal of Rare Diseases | PI3K/AKT/mTOR Pathway in Vascular Malformations

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This article systematically reviews the molecular mechanisms of the PI3K/AKT/mTOR signaling pathway in vascular malformations and its potential as a therapeutic target. It also summarizes the progress of multiple inhibitors targeting this pathway in clinical trials, providing theoretical and clinical basis for targeted therapy of refractory vascular malformations.

 

Literature Overview

This article, titled 'PI3K/AKT/mTOR axis in vascular malformations: from molecular insights to targeted clinical trials', published in Orphanet Journal of Rare Diseases, reviews and summarizes the pathogenic mechanisms of the PI3K/AKT/mTOR signaling pathway in various vascular malformations and explores its potential as a therapeutic target. The article also analyzes the dual role of this pathway in slow-flow and fast-flow vascular malformations and integrates data from multiple clinical trials to evaluate the therapeutic prospects of mTOR and PI3K inhibitors. The content provides important theoretical support for clinical intervention strategies and offers directions for optimizing future targeted therapies.

Background Knowledge

Vascular malformations are a group of diseases caused by congenital abnormalities in vascular structures, including venous malformations (VM), lymphatic malformations (LM), and arteriovenous malformations (AVM). These conditions are often accompanied by chronic pain, functional impairment, and severe cosmetic deformities, and in severe cases, can be life-threatening. Despite their clinical heterogeneity, recent molecular genetic studies have identified aberrant activation of the PI3K/AKT/mTOR pathway as one of the core pathogenic mechanisms in various vascular malformations, especially in the context of mutations in genes such as PIK3CA, TEK, and PTEN. This pathway plays a critical role in regulating endothelial cell proliferation, migration, metabolism, and cytoskeletal remodeling, making it an important target for therapeutic intervention. Several mTOR inhibitors, such as Sirolimus, and PI3Kα-specific inhibitors, such as Alpelisib, have already shown preliminary efficacy in clinical trials. However, feedback regulation of the pathway, the correlation between genotype and phenotype, drug resistance, and long-term efficacy maintenance remain major research challenges. This article aims to integrate current molecular mechanisms and clinical trial progress to provide a reference framework for future precision therapy.

 

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Research Methods and Experiments

This article mainly employs a literature review approach to systematically analyze the molecular mechanisms of the PI3K/AKT/mTOR signaling pathway in vascular malformations and integrates data from multiple clinical trials to evaluate its feasibility as a therapeutic target. The study provides a detailed analysis of the functions of core molecules such as PI3K, AKT, and mTOR in cellular signal transduction and how their mutations or abnormal activation affect endothelial cell behavior. Additionally, it explores the regulatory role of PTEN as a negative modulator in the pathway and the involvement of feedback regulation in the development of drug resistance. Clinical trial data, including treatment outcomes, adverse effects, and indications for Sirolimus and Alpelisib at different stages, are summarized to assess their efficacy and safety in patients with vascular malformations.

Key Findings and Perspectives

• The PI3K/AKT/mTOR pathway is broadly dysregulated in vascular malformations and serves as a central pathway influenced by multiple mutated genes (e.g., PIK3CA, TEK, AKT1, PTEN)
• This pathway regulates endothelial cell proliferation, migration, metabolism, and angiogenesis. Its hyperactivation is associated with both slow-flow and fast-flow vascular malformations (e.g., AVM)
• Sirolimus has shown significant therapeutic effects in various slow-flow vascular malformations (e.g., VM, LM, PROS), particularly with rapid symptom relief observed in pediatric patients
• Alpelisib, a PI3Kα-specific inhibitor, demonstrates potential for effective disease control in patients with PROS and CLVM
• Despite the observed clinical benefits of Sirolimus and Alpelisib, drug resistance and long-term toxicity remain key challenges, suggesting the need for more specific inhibitors or combination therapy strategies
• Recent studies identify mTORC3 as a newly discovered complex. Its components and regulatory mechanisms remain incompletely understood, potentially offering novel insights for future drug development

Significance and Future Directions

This study provides a molecular mechanism-based therapeutic strategy for refractory vascular malformations and offers theoretical support for personalized treatment (e.g., drug selection based on gene mutations). Future research should further explore the dynamic regulatory network of the pathway, the genotype-phenotype correlations, and develop mutation subtype-specific inhibitors to enhance therapeutic efficacy and reduce systemic side effects. Moreover, balancing long-term pathway inhibition with normal physiological functions, overcoming drug resistance, and exploring combination therapies with other signaling pathways remain important directions in translational medicine.

 

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Conclusion

This article systematically summarizes the role of the PI3K/AKT/mTOR pathway in vascular malformations, highlighting its importance as a core pathogenic mechanism and therapeutic target. Through in-depth analysis of the molecular mechanisms, including correlations between mutations (e.g., PIK3CA, TEK, PTEN) and phenotypes, as well as the clinical performance of multiple inhibitors, the article emphasizes the broad impact of the pathway's regulatory network on both slow-flow and fast-flow vascular malformations. Sirolimus and Alpelisib, as major mTOR and PI3Kα inhibitors, have shown therapeutic potential in clinical trials, yet challenges related to drug resistance, side effects, and long-term efficacy remain. Future research should focus on feedback mechanisms within the pathway, genotype-phenotype relationships, and the development of more selective small-molecule inhibitors to improve the therapeutic index. Additionally, integrating bioinformatics tools with clinical data to advance precision medicine strategies, such as genotype-guided drug selection, will be a key direction for the field. This review provides valuable mechanistic and therapeutic insights for clinicians and researchers, particularly offering new molecular-targeted intervention strategies for refractory cases.

 

Yuan-Yang Zheng, Chen Hua, and Xiao-Xi Lin. PI3K/AKT/mTOR axis in vascular malformations: from molecular insights to targeted clinical trials. Orphanet Journal of Rare Diseases.