Targeted therapy for capillary-venous malformations PMID: 38880808

ADC Targets in Oncology

2026-04-10

Targeted therapy for capillary-venous malformations

Signal Transduct Target Ther. 2024 Jun 17;9(1):146. doi: 10.1038/s41392-024-01862-9.

Lola Zerbib ¹ ² , Sophia Ladraa ¹ ² , Antoine Fraissenon ² ³ ⁴ ⁵ , Charles Bayard ¹ ² , Marina Firpion ¹ ² , Quitterie Venot ¹ ² , Sanela Protic ¹ ² , Clément Hoguin ¹ ² , Amandine Thomas ² , Sylvie Fraitag ⁶ , Jean-Paul Duong ¹ ⁶ , Sophie Kaltenbach ⁷ , Estelle Balducci ¹ ⁷ , Coline Lefevre ⁷ , Patrick Villarese ⁷ , Vahid Asnafi ¹ ² ⁷ , Christine Broissand ⁸ , Nicolas Goudin ⁹ , Ivan Nemazanyy ¹⁰ , Gwennhael Autret ¹¹ , Bertrand Tavitian ¹¹ , Christophe Legendre ¹ ² ¹² , Nadia Arzouk ¹³ , Veronique Minard-Colin ¹⁴ , Caroline Chopinet ¹⁵ , Michael Dussiot ¹⁶ , Denise M Adams ¹⁷ , Tristan Mirault ¹ ¹⁸ , Laurent Guibaud ² ³ , Paul Isenring ¹⁹ , Guillaume Canaud ²⁰ ²¹ ²² ²³

Affiliations

1. Université Paris Cité, Paris, France.
2. INSERM U1151, Institut Necker-Enfants Malades, Paris, France.
3. Service d'Imagerie Pédiatrique, Hôpital Femme-Mère-Enfant, HCL, Bron, France.
4. CREATIS UMR 5220, Villeurbanne, 69100, France.
5. Service de Radiologie Mère-Enfant, Hôpital Nord, Saint Etienne, France.
6. Service d'Anatomie pathologique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
7. Laboratoire d'Oncohématologie, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
8. Pharmacie, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
9. Necker Bio-Image Analysis, INSERM US24/CNRS UMS 3633, Paris, France.
10. Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633, Paris, France.
11. Plateforme Imageries du Vivant, Université de Paris, PARCC, INSERM, Paris, France.
12. Service de Néphrologie, Transplantation Adultes, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
13. Service de Transplantation, Hôpital La Pitié Salpétrière, AP-HP, Paris, France.
14. Department of Pediatric and Adolescent Oncology, INSERM 1015, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
15. Service de Physiologie & Explorations Fonctionnelles Cardiovasculaires, CHU de Lille, Lille, 59000, France.
16. INSERM U1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Laboratoire d'Excellence GR-Ex, Paris, France.
17. Division of Oncology, Comprehensive Vascular Anomalies Program, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
18. Service de Médecine Vasculaire, hôpital Européen Georges-Pompidou, Paris, France.
19. Nephrology Research Group, L'Hôtel-Dieu de Québec Research Center, Department of Medicine, Faculty of Medicine, Laval University, Quebec, QC, G1R2J6, Canada.
20. Université Paris Cité, Paris, France. [email protected].
21. INSERM U1151, Institut Necker-Enfants Malades, Paris, France. [email protected].
22. Unité de médecine translationnelle et thérapies ciblées, Hôpital Necker-Enfants Malades, AP-HP, Paris, France. [email protected].
23. CNRS UMR8253, Institut Necker-Enfants Malades, Paris, France. [email protected].

Abstract

Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK, an endothelial transmembrane receptor signaling through PIK3CA. Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations. Here, we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient phenotypes. We showed that these malformations only partially signal through Akt proteins. We compared the efficacy of different drugs, including rapamycin, a mTORC1 Inhibitor, miransertib, an Akt Inhibitor and alpelisib, a PI3Kα Inhibitor at improving the lesions seen in the mouse model. We demonstrated the effectiveness of alpelisib in preventing vascular malformations' occurrence, improving the already established ones, and prolonging survival. Considering these findings, we were authorized to treat 25 patients with alpelisib, including 7 children displaying PIK3CA (n = 16) or TEK (n = 9)-related capillary venous malformations resistant to usual therapies including sirolimus, debulking surgical procedures or percutaneous sclerotherapies. We assessed the volume of vascular malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib demonstrated improvement in all 25 patients. Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively, over 6 months on alpelisib. In conclusion, this study supports PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations.