A review of mechanisms of disease across <i>PIK3CA</i>-related disorders with vascular manifestations

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Abstract

Background

PIK3CA-related disorders include vascular malformations and overgrowth of various tissues that are caused by postzygotic, somatic variants in the gene encoding phosphatidylinositol-3-kinase (PI3K) catalytic subunit alpha. These mutations result in activation of the PI3K/AKT/mTOR signaling pathway. The goals of this review are to provide education on the underlying mechanism of disease for this group of rare conditions and to summarize recent advancements in the understanding of, as well as current and emerging treatment options for PIK3CA-related disorders.

Main body

PIK3CA-related disorders include PIK3CA-related overgrowth spectrum (PROS), PIK3CA-related vascular malformations, and PIK3CA-related nonvascular lesions. Somatic activating mutations (predominantly in hotspots in the helical and kinase domains of PIK3CA, but also in other domains), lead to hyperactivation of the PI3K signaling pathway, which results in abnormal tissue growth. Diagnosis is complicated by the variability and overlap in phenotypes associated with PIK3CA-related disorders and should be performed by clinicians with the required expertise along with coordinated care from a multidisciplinary team. Although tissue mosaicism presents challenges for confirmation of PIK3CA mutations, next-generation sequencing and tissue selection have improved detection. Clinical improvement, radiological response, and patient-reported outcomes are typically used to assess treatment response in clinical studies of patients with PIK3CA-related disorders, but objective assessment of treatment response is difficult using imaging (due to the heterogeneous nature of these disorders, superimposed upon patient growth and development). Despite their limitations, patient-reported outcome tools may be best suited to gauge patient improvement. New therapeutic options are needed to provide an alternative or supplement to standard approaches such as surgery and sclerotherapy. Currently, there are no systemic agents that have regulatory approval for these disorders, but the mTOR inhibitor sirolimus has been used for several years in clinical trials and off label to address symptoms. There are also other agents under investigation for PIK3CA-related disorders that act as inhibitors to target different components of the PI3K signaling pathway including AKT (miransertib) and PI3K alpha (alpelisib).

Conclusion

Management of patients with PIK3CA-related disorders requires a multidisciplinary approach. Further results from ongoing clinical studies of agents targeting the PI3K pathway are highly anticipated.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13023-021-01929-8.

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Most cited references 73

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The PI3K Pathway in Human Disease.

David A. Fruman, Honyin Chiu, Benjamin D Hopkins … (2017)

Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.

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Targeting the phosphoinositide 3-kinase pathway in cancer.

Pixu Liu, Hailing Cheng, Thomas M. Roberts … (2009)

The phosphoinositide 3-kinase (PI3K) pathway is a key signal transduction system that links oncogenes and multiple receptor classes to many essential cellular functions, and is perhaps the most commonly activated signalling pathway in human cancer. This pathway therefore presents both an opportunity and a challenge for cancer therapy. Even as inhibitors that target PI3K isoforms and other major nodes in the pathway, including AKT and mammalian target of rapamycin (mTOR), reach clinical trials, major issues remain. Here, we highlight recent progress that has been made in our understanding of the PI3K pathway and discuss the potential of and challenges for the development of therapeutic agents that target this pathway in cancer.

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Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies.

Michel Wassef, Francine Blei, Denise Adams … (2015)

Vascular anomalies represent a spectrum of disorders from a simple "birthmark" to life- threatening entities. Incorrect nomenclature and misdiagnoses are commonly experienced by patients with these anomalies. Accurate diagnosis is crucial for appropriate evaluation and management, often requiring multidisciplinary specialists. Classification schemes provide a consistent terminology and serve as a guide for pathologists, clinicians, and researchers. One of the goals of the International Society for the Study of Vascular Anomalies (ISSVA) is to achieve a uniform classification. The last classification (1997) stratified vascular lesions into vascular malformations and proliferative vascular lesions (tumors). However, additional disease entities have since been identified that are complex and less easily classified by generic headings, such as capillary malformation, venous malformation, lymphatic malformation, etc. We hereby present the updated official ISSVA classification of vascular anomalies. The general biological scheme of the classification is retained. The section on tumors has been expanded and lists the main recognized vascular tumors, classified as benign, locally aggressive or borderline, and malignant. A list of well-defined diseases is included under each generic heading in the "Simple Vascular Malformations" section. A short definition is added for eponyms. Two new sections were created: one dealing with the malformations of individually named vessels (previously referred to as "truncular" malformations); the second groups lesions of uncertain or debated nature (tumor versus malformation). The known genetic defects underlying vascular anomalies are included in an appendix. This classification is meant to be a framework, acknowledging that it will require modification as new scientific information becomes available.

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Author and article information

Contributors

Guillaume Canaud:

ORCID: http://orcid.org/0000-0001-8146-7996

guillaume.canaud@inserm.fr

Journal

Journal ID (nlm-ta): Orphanet J Rare Dis

Journal ID (iso-abbrev): Orphanet J Rare Dis

Title: Orphanet Journal of Rare Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1750-1172

Publication date (Electronic): 8 July 2021

Publication date PMC-release: 8 July 2021

Publication date Collection: 2021

Volume: 16

Electronic Location Identifier: 306

Affiliations

[1 ]GRID grid.508487.6, ISNI 0000 0004 7885 7602, Overgrowth Syndrome and Vascular Anomalies Unit, Hôpital Necker Enfants Malades, INSERM U1151, Assistance Publique-Hôpitaux de Paris, , Université de Paris, ; 149 rue de Sèvres, 75105 Paris, France

[2 ]GRID grid.24827.3b, ISNI 0000 0001 2179 9593, Division of Hematology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, , University of Cincinnati College of Medicine, ; Cincinnati, OH USA

[3 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Division of Oncology, Comprehensive Vascular Anomalies Program, Children’s Hospital of Philadelphia, , Perelman School of Medicine and the University of Pennsylvania, ; Philadelphia, PA USA

[4 ]GRID grid.7942.8, ISNI 0000 0001 2294 713X, Human Molecular Genetics, de Duve Institute, , University of Louvain, ; Brussels, Belgium

[5 ]GRID grid.7942.8, ISNI 0000 0001 2294 713X, Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint Luc, , University of Louvain, ; Brussels, Belgium

[6 ]GRID grid.411119.d, ISNI 0000 0000 8588 831X, VASCERN VASCA European Reference Centre, , Bichat-Claude Bernard Hospital, ; Paris, France

[7 ]GRID grid.7942.8, ISNI 0000 0001 2294 713X, Walloon Excellence in Lifesciences and Biotechnology (WELBIO), , University of Louvain, ; Brussels, Belgium

[8 ]GRID grid.14003.36, ISNI 0000 0001 2167 3675, Division of Genetics and Metabolism, Department of Pediatrics, , University of Wisconsin School of Medicine and Public Health, ; Madison, WI USA

Author information

Guillaume Canaud http://orcid.org/0000-0001-8146-7996

Article

Publisher ID: 1929

DOI: 10.1186/s13023-021-01929-8

PMC ID: 8268514

PubMed ID: 34238334

SO-VID: 24c1a38b-2988-4463-8bbd-d1bad10e8e04

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 25 March 2021

Date accepted : 27 June 2021

Custom metadata

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: pik3ca,pi3k,pros,vascular malformation,sirolimus,alpelisib,miransertib

Data availability:

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: pik3ca, pi3k, pros, vascular malformation, sirolimus, alpelisib, miransertib

A review of mechanisms of disease across PIK3CA-related disorders with vascular manifestations

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Abstract

Background

Main body

Conclusion

Supplementary Information

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IEEE: COVID-19 related research

Most cited references 73

The PI3K Pathway in Human Disease.

Targeting the phosphoinositide 3-kinase pathway in cancer.

Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies.

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