Targeted therapy in patients with PIK3CA-related overgrowth syndrome

@article{Venot2018TargetedTI,
  title={Targeted therapy in patients with PIK3CA-related overgrowth syndrome},
  author={Quitterie Venot and Thomas Blanc and Smail Hadj Rabia and Laureline Berteloot and Sophia Ladraa and Jean-Paul Duong and Estelle Blanc and Simon C Johnson and Cl{\'e}ment Hoguin and Olivia Boccara and Sabine Sarnacki and Nathalie Boddaert and St{\'e}phanie Pannier and Frank Egu{\'i}a Mart{\'i}nez 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 Soupre and Stanislas Lyonnet and J{\'e}r{\'e}my Sadoine and Lotfi Slimani and Catherine Chaussain and C{\'e}cile Laroche-Raynaud and Laurent Guibaud and Christine Broissand and Jeanne Amiel and Christophe M Legendre and Fabiola Terzi and Guillaume Canaud},
  journal={Nature},
  year={2018},
  volume={558},
  pages={540-546}
}
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. [...] Key Method 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…Expand
Genetic disorders: PI3K inhibitor reverses overgrowth syndrome
TLDR
These findings support the repurposing of PIK3CA inhibitors in the treatment of PROS and show that a smallmolecule inhibitor of Pik3CA rescues the PROS phenotype in a novel mouse disease model. Expand
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Multidisciplinary care is essential for comfort and functional gains in patients with CLOVES syndrome, particularly those with severe symptoms, and close monitoring while on sirolimus medical therapy combined with frequent reassessment of orthopedic needs can dramatically improve patient quality of life and outcomes. Expand
PIK3CA vascular overgrowth syndromes: an update.
TLDR
An update on the clinical features, complications, and management strategies for the PIK3CA-related overgrowth spectrum (PROS), a heterogenous group of disorders with complications related to the tissues harboring the mutation. Expand
Clinical experience with the AKT1 inhibitor miransertib in two children with PIK3CA-related overgrowth syndrome
TLDR
This case series highlights the potential therapeutic utility of miransertib in selected paediatric patients with severe PROS, and further demonstrates the potential for re-purposing targeted therapies for the treatment of rare diseases. Expand
Rheumatoid Arthritis and CLOVES Syndrome: A Tricky Diagnosis
TLDR
The case of a young female patient, with anti-citrullinated peptide antibodies-positive rheumatoid arthritis, referred for persistent finger pain and stiffness, revealed mild dysmorphic features with early-onset and the history of surgeries for thoracic lipoma and venous malformation that were strongly suggestive of CLOVES syndrome. Expand
PIK3CA-Related Overgrowth Spectrum From Diagnosis to Targeted Therapy: A Case of CLOVES Syndrome Treated With Alpelisib
TLDR
The effect of Alpelisib (BYL719), a specific inhibitor for the p110α subunit of PI3K, was shown in patients with PROS disorders who had severe or life-threatening complications and were not sensitive to any other treatment. Expand
CLOVES Syndrome in a Nine-month-old Infant
TLDR
A case of CLOVES syndrome is described in a nine-month-old male infant who was referred to the dermatology clinic for further assessment and management and the diagnosis was made based on clinical findings and confirmed by genetic testing. Expand
Reductive Otoplasty and Facial Debulking in a Pediatric Patient With PIK3CA-Related Overgrowth
Overgrowth syndromes encompass a number of rare genetic diseases with heterogeneous clinical phenotypes. Accordingly, there is a strong imperative to collect data and classify these disorders to aidExpand
Treatment strategies for mosaic overgrowth syndromes of the PI3K-AKT-mTOR pathway.
TLDR
This review aims to describe the clinical and molecular characteristics of the main OS involving the PI3K-AKT-mTOR pathway, along with the treatments available or under development, and summarizes available data regarding OS. Expand
Prenatal imaging diagnosis of PIK3CA‐related overgrowth spectrum disorders in first trimester with emphasis on extremities
TLDR
A case of PROS diagnosed in the first trimester is reported and the imaging findings, particularly anomalies of the extremities, which should raise the suspicion of this congenital spectrum, that is represented mainly by focal overgrowth. Expand
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References

SHOWING 1-10 OF 27 REFERENCES
Clinical Delineation and Natural History of the PIK3CA-Related Overgrowth Spectrum**
TLDR
The phenotypic data show that these previously described disease entities have considerable overlap, and represent a spectrum that overlaps with Proteus syndrome, and this spectrum can be distinguished by the absence of cerebriform connective tissue nevi and a distinct natural history. Expand
PIK3CA‐related overgrowth spectrum (PROS): Diagnostic and testing eligibility criteria, differential diagnosis, and evaluation
TLDR
The phenotypic spectrum associated with different genotypes and mutation burdens was characterized, including a better understanding of associated complications and natural history, and preliminary recommendations for a uniform approach to assessment of overgrowth and molecular diagnostic testing were determined. Expand
Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome.
TLDR
It is concluded that CLOVES is caused by postzygotic activating mutations in PIK3CA, which have been identified in cancer cells, in which they increase phosphoinositide-3-kinase activity. Expand
Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans
TLDR
A causal relationship between activating Pik3ca mutations and the genesis of VMs is demonstrated, and a genetic model that faithfully mirrors the normal etiology and development of this human disease is provided, establishing the basis for the use of PI3K-targeted therapies in VMs. Expand
Inhibition of the mTORC pathway in the antiphospholipid syndrome.
TLDR
The results suggest that the mTORC pathway is involved in the vascular lesions associated with the antiphospholipid syndrome. Expand
PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution
TLDR
The molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations. Expand
Ubiquitous expression of the Pik3caH1047R mutation promotes hypoglycemia, hypoinsulinemia, and organomegaly
TLDR
This mouse model demonstrates the critical role of PI3K in the regulation of both organ size and glucose metabolism at the whole animal level and indicates that both the growth and metabolic functions of constitutive PI2K activity can be Akt2 independent. Expand
Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials
TLDR
The biologic properties of the 2-aminothiazole derivative NVP-BYL719, a selective inhibitor of PI3Kα and its most common oncogenic mutant forms, are reported and it is found that PIK3CA mutation was the foremost positive predictor of sensitivity while revealing additional positive and negative associations such as Pik3CA amplification and PTEN mutation, respectively. Expand
A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2− Metastatic Breast Cancer
TLDR
The combination of letrozole and alpelisib was safe, with reversible toxicities, and clinical activity was observed independently of Pik3CA mutation status, although clinical benefit was seen in a higher proportion of patients with PIK3CA-mutated tumors. Expand
Heterozygous expression of the oncogenic Pik3ca(H1047R) mutation during murine development results in fatal embryonic and extraembryonic defects.
TLDR
The results confirm the lethality associated with heterozygous expression of the Pik3ca(H1047R) mutation during development and likely explain the lack of inherited germline PIK3CA mutations in humans. Expand
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