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Targeted therapy in patients with PIK3CA-related overgrowth syndrome
Quitterie Venot1, Thomas Blanc1,2,3, Smail Hadj Rabia2,4,5
1INSERM U1151, Institut Necker Enfants Malades, Paris, France.
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.
Insights
CLOVES syndrome, a rare genetic disorder, is effectively treated with PIK3CA inhibition. This PIK3CA-related overgrowth syndrome (PROS) treatment showed significant symptom improvement and reduced organ dysfunction in patients.
Area of Science:
- Genetics and Molecular Biology
- Medical Genetics
- Pharmacology
Background:
- CLOVES syndrome is a rare genetic disorder caused by PIK3CA gene mutations, belonging to the PIK3CA-related overgrowth syndromes (PROS) spectrum.
- This condition has limited treatment options and a poor prognosis.
- Existing treatments for PROS are often ineffective.
Observation:
- A postnatal mouse model partially replicated human PROS/CLOVES, demonstrating organ dysfunction.
- BYL719, a PIK3CA inhibitor, showed efficacy in preventing and improving organ dysfunction in the mouse model.
- Nineteen patients with PROS received BYL719 treatment.
Findings:
- BYL719 treatment improved all observed PROS symptoms in patients.
- Vascular tumors diminished, congestive heart failure improved, hemihypertrophy reduced, and scoliosis attenuated.
- The treatment was well-tolerated with no significant adverse effects.
Implications:
- PIK3CA inhibition represents a promising therapeutic strategy for CLOVES syndrome and other PROS conditions.
- This study provides the first direct clinical evidence supporting PIK3CA inhibitors for PROS.
- Targeted therapy offers new hope for patients with previously intractable symptoms.
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