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.

Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis

“…These include pan‐PI3K and PI3K isoform‐selective inhibitors; a PI3K inhibitor that is selective for the δ isoform, idelalisib, is now approved for the treatment of chronic lymphocytic leukemia, relapsed follicular B‐cell non‐Hodgkin lymphoma, and relapsed small lymphocytic lymphoma. BYL719 (alpelisib) is a specific inhibitor of the PI3K isoform α (encoded by PIK3CA gene) that has shown some early promise in PI3K‐altered solid tumors and in patients with CLOVES . ARQ092 (miransertib) is a new allosteric inhibitor of AKT that is orally bioavailable and has a manageable safety profile in patients with advanced solid tumors.…”

“…We used some standard inhibitors of PI3K (LY290042), mTOR (rapamycin), and ERK (U0126), as well as a new PI3Kα‐selective inhibitor, BYL719 (alpelisib), and a pan‐AKT (protein kinase B) inhibitor, ARQ092 (miransertib) . BYL719 and ARQ092 have shown some early promise in preclinical studies and early phase of clinical trials …”

Clinical application of molecular genetics in lymphatic malformations

“…Better understanding the pharmacology of sirolimus in the setting of specific PIK3CA mutations in HNLM tissue is the only way to predict the efficacy of sirolimus. It may be that inhibition of other components of the PI3K pathway are more effective for treatment of HNLM …”

“…It may be that inhibition of other components of the PI3K pathway are more effective for treatment of HNLM. 36 Another consideration is genetic testing to direct HNLM therapy with selective use of surgery to remove all cells with mutations in smaller HNLM. There are many phenotypic presentations of HNLM and some may not need combined medical and surgical therapy; instead, these lesions could be managed with surgical excision alone, potentially avoiding any biologic agents and their associated adverse effects.…”

Rare disease specialists and clinical pharmacologists unite: Increase collection of longitudinal data!

“…These diseases are relatively frequent, have features which can be readily measured, and are clearly progressive, although the variability of the time course is considerable. When the endpoint is easily accessible, such as in PIK3CA ‐related disorders, where gain‐of‐function mutations lead to overgrowth of affected tissue, spectacular treatment effects can be shown even in the presence of variable disease without data on the natural history . However, there are many other rare diseases, such as NDDs, for which such endpoints are not readily available.…”