Targeted therapy in patients with PIK3CA-related overgrowth syndrome

Quitterie Venot; Thomas Blanc; Smail Hadj Rabia; Laureline Berteloot; Sophia Ladraa; Jean-Paul Duong; Estelle Blanc; Simon C Johnson; Clément Hoguin; Olivia Boccara; Sabine Sarnacki; Nathalie Boddaert; Stephanie Pannier; Frank Martinez; Sato Magassa; Junna Yamaguchi; Bertrand Knebelmann; Pierre Merville; Nicolas Grenier; Dominique Joly; Valérie Cormier-Daire; Caroline Michot; Christine Bole-Feysot; Arnaud Picard; Véronique Soupre; Stanislas Lyonnet; Jeremy Sadoine; Lotfi Slimani; Catherine Chaussain; Cécile Laroche-Raynaud; Laurent Guibaud; Christine Broissand; Jeanne Amiel; Christophe Legendre; Fabiola Terzi; Guillaume Canaud

doi:10.1038/s41586-018-0217-9

Targeted therapy in patients with PIK3CA-related overgrowth syndrome

Quitterie Venot, Thomas Blanc, Smail Hadj Rabia, Laureline Berteloot, Sophia Ladraa, Jean-Paul Duong, Estelle Blanc, Simon C Johnson, Clément Hoguin, Olivia Boccara, Sabine Sarnacki, Nathalie Boddaert, Stephanie Pannier, Frank Martinez, Sato Magassa, Junna Yamaguchi, Bertrand Knebelmann, Pierre Merville, Nicolas Grenier, Dominique JolyValérie Cormier-Daire, Caroline Michot, Christine Bole-Feysot, Arnaud Picard, Véronique Soupre, Stanislas Lyonnet, Jeremy Sadoine, Lotfi Slimani, Catherine Chaussain, Cécile Laroche-Raynaud, Laurent Guibaud, Christine Broissand, Jeanne Amiel, Christophe Legendre, Fabiola Terzi, Guillaume Canaud

Research output: Contribution to journal › Article › peer-review

377 Citations (Scopus)

Abstract

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

Original language	English
Pages (from-to)	540-546
Number of pages	7
Journal	Nature
Volume	558
Issue number	7711
DOIs	https://doi.org/10.1038/s41586-018-0217-9
Publication status	Published - Jun 2018
Externally published	Yes

Keywords

Adult
Animals
Child
Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors
Disease Models, Animal
Female
HeLa Cells
Heart Failure/complications
Humans
Lipoma/drug therapy
Male
Mice
Molecular Targeted Therapy
Musculoskeletal Abnormalities/drug therapy
Nevus/drug therapy
Phenotype
Scoliosis/complications
Sirolimus/therapeutic use
Syndrome
Thiazoles/therapeutic use
Vascular Malformations/drug therapy
Vascular Neoplasms/complications

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41586-018-0217-9

Cite this

Venot, Q., Blanc, T., Rabia, S. H., Berteloot, L., Ladraa, S., Duong, J.-P., Blanc, E., Johnson, S. C., Hoguin, C., Boccara, O., Sarnacki, S., Boddaert, N., Pannier, S., Martinez, F., Magassa, S., Yamaguchi, J., Knebelmann, B., Merville, P., Grenier, N., ... Canaud, G. (2018). Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature, 558(7711), 540-546. https://doi.org/10.1038/s41586-018-0217-9

@article{e0aa381e74814aa094d06e2f7b0de0f1,

title = "Targeted therapy in patients with PIK3CA-related overgrowth syndrome",

abstract = "CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.",

keywords = "Adult, Animals, Child, Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors, Disease Models, Animal, Female, HeLa Cells, Heart Failure/complications, Humans, Lipoma/drug therapy, Male, Mice, Molecular Targeted Therapy, Musculoskeletal Abnormalities/drug therapy, Nevus/drug therapy, Phenotype, Scoliosis/complications, Sirolimus/therapeutic use, Syndrome, Thiazoles/therapeutic use, Vascular Malformations/drug therapy, Vascular Neoplasms/complications",

author = "Quitterie Venot and Thomas Blanc and Rabia, {Smail Hadj} and Laureline Berteloot and Sophia Ladraa and Jean-Paul Duong and Estelle Blanc and Johnson, {Simon C} and Cl{\'e}ment Hoguin and Olivia Boccara and Sabine Sarnacki and Nathalie Boddaert and Stephanie Pannier and Frank Martinez and Sato Magassa and Junna Yamaguchi and Bertrand Knebelmann and Pierre Merville and Nicolas Grenier and Dominique Joly and Val{\'e}rie Cormier-Daire and Caroline Michot and Christine Bole-Feysot and Arnaud Picard and V{\'e}ronique Soupre and Stanislas Lyonnet and Jeremy Sadoine and Lotfi Slimani and Catherine Chaussain and C{\'e}cile Laroche-Raynaud and Laurent Guibaud and Christine Broissand and Jeanne Amiel and Christophe Legendre and Fabiola Terzi and Guillaume Canaud",

year = "2018",

month = jun,

doi = "10.1038/s41586-018-0217-9",

language = "English",

volume = "558",

pages = "540--546",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7711",

}

Venot, Q, Blanc, T, Rabia, SH, Berteloot, L, Ladraa, S, Duong, J-P, Blanc, E, Johnson, SC, Hoguin, C, Boccara, O, Sarnacki, S, Boddaert, N, Pannier, S, Martinez, F, Magassa, S, Yamaguchi, J, Knebelmann, B, Merville, P, Grenier, N, Joly, D, Cormier-Daire, V, Michot, C, Bole-Feysot, C, Picard, A, Soupre, V, Lyonnet, S, Sadoine, J, Slimani, L, Chaussain, C, Laroche-Raynaud, C, Guibaud, L, Broissand, C, Amiel, J, Legendre, C, Terzi, F & Canaud, G 2018, 'Targeted therapy in patients with PIK3CA-related overgrowth syndrome', Nature, vol. 558, no. 7711, pp. 540-546. https://doi.org/10.1038/s41586-018-0217-9

TY - JOUR

T1 - Targeted therapy in patients with PIK3CA-related overgrowth syndrome

AU - Venot, Quitterie

AU - Blanc, Thomas

AU - Rabia, Smail Hadj

AU - Berteloot, Laureline

AU - Ladraa, Sophia

AU - Duong, Jean-Paul

AU - Blanc, Estelle

AU - Johnson, Simon C

AU - Hoguin, Clément

AU - Boccara, Olivia

AU - Sarnacki, Sabine

AU - Boddaert, Nathalie

AU - Pannier, Stephanie

AU - Martinez, Frank

AU - Magassa, Sato

AU - Yamaguchi, Junna

AU - Knebelmann, Bertrand

AU - Merville, Pierre

AU - Grenier, Nicolas

AU - Joly, Dominique

AU - Cormier-Daire, Valérie

AU - Michot, Caroline

AU - Bole-Feysot, Christine

AU - Picard, Arnaud

AU - Soupre, Véronique

AU - Lyonnet, Stanislas

AU - Sadoine, Jeremy

AU - Slimani, Lotfi

AU - Chaussain, Catherine

AU - Laroche-Raynaud, Cécile

AU - Guibaud, Laurent

AU - Broissand, Christine

AU - Amiel, Jeanne

AU - Legendre, Christophe

AU - Terzi, Fabiola

AU - Canaud, Guillaume

PY - 2018/6

Y1 - 2018/6

N2 - CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

AB - CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

KW - Adult

KW - Animals

KW - Child

KW - Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors

KW - Disease Models, Animal

KW - Female

KW - HeLa Cells

KW - Heart Failure/complications

KW - Humans

KW - Lipoma/drug therapy

KW - Male

KW - Mice

KW - Molecular Targeted Therapy

KW - Musculoskeletal Abnormalities/drug therapy

KW - Nevus/drug therapy

KW - Phenotype

KW - Scoliosis/complications

KW - Sirolimus/therapeutic use

KW - Syndrome

KW - Thiazoles/therapeutic use

KW - Vascular Malformations/drug therapy

KW - Vascular Neoplasms/complications

U2 - 10.1038/s41586-018-0217-9

DO - 10.1038/s41586-018-0217-9

M3 - Article

C2 - 29899452

SN - 0028-0836

VL - 558

SP - 540

EP - 546

JO - Nature

JF - Nature

IS - 7711

ER -

Targeted therapy in patients with PIK3CA-related overgrowth syndrome

Abstract

Keywords

UN SDGs

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