Tue. May 24th, 2022

New therapeutic perspectives for patients with lymphatic abnormalities associated with a mutation in the PIK3CA gene

3D anatomy of the lymphatic system. Credit: Fotalia

The team at the Department of Adult Nephrology-Kidney Transplant at Necker-Enfants Malades AP-HP Hospital, Inserm and the University of Paris has carried out work, coordinated by Prof. Guillaume Canaud, who opens up new therapeutic perspectives for patients with lymphatic abnormalities associated with a mutation in PIK3CA -genet.

The results of this study were published on October 6, 2021 in the journal Scientific translational medicine .

Lymphatic malformations, formerly called lymphangiomas, are malformations of the lymphatic system that can be localized (cutaneous, subcutaneous, or mucous membrane) or more rarely spread throughout the body. They are most often congenital and visible before the age of two. They are often located in the axillary and cervical areas. These malformations may be accompanied by painful “inflammatory flare-ups”, compression of organs, especially in the trachea, necessitating the installation of a tracheotomy, diffuse outflow into the pleura or severe infection. They can sometimes be life threatening. These malformations very often have a significant aesthetic impact and a strong impact on the integration of patients into society.

In the vast majority of cases, lymphatic malformations are due to a mutation in the PIK3CA gene acquired during embryonic development (in utero). Current treatments are based on percutaneous sclerosis guided by radiology and / or often overdue surgeries. They can be combined with supportive care such as corticosteroids for the treatment of flare-ups, painkillers, antibiotics, nightly respiratory support and nutritional and psychological support. In some cases, an immunosuppressive therapy, rapamycin sirolimus, is used with varying effectiveness. There is currently no approved treatment for this indication.

Credit: National Institute of Health and Medical Research

The team created the first mouse model carrying a mutation in the PIK3CA gene specifically in lymphatic vessels, which reproduces the different types of lymphatic malformations that patients present. This experimental model can develop highly localized or, on the contrary, very diffuse malformations depending on the needs.

The team then identified alpelisib (BYL719), a specific inhibitor of PIK3CA, and demonstrated its role as a therapeutic molecule of interest in this preclinical model. With very promising results in animals, the researchers then treated six patients, three children and three adults with severe lymphatic malformations secondary to a PIK3CA mutation that had resisted conventional treatments.

At six months, treatment with alplesib was accompanied by an improvement in patients’ symptoms (pain, inflammatory flare-ups, oozing, swallowing discomfort, etc.) and a 48% reduction in the amount of malformations measured by MRI. As previously reported in another indication, the treatment was well tolerated.

This work, thanks to the new experimental model created, makes it possible to better understand the pathophysiology of lymphatic malformations, but above all opens up new very promising therapeutic perspectives.


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More information:
Florence Delestre et al, administration of Alpelisib reduced lymphatic malformations in a mouse model and in patients Scientific translational medicine (2021). DOI: 10.1126 / scitranslmed.abg0809

Provided by the National Institute of Health and Medical Research

Citation: New therapeutic perspectives for patients with lymphatic abnormalities associated with a mutation in the PIK3CA gene (2021, October 7) retrieved October 8, 2021 from https://medicalxpress.com/news/2021-10-therapeutic-perspectives-patients- lymphatic abnormalities.html

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