Therapeutics: Phosphoinositide 3-kinase α (PI3Kα); phosphoinositide 3-kinase catalytic subunit α polypeptide (PI3KCA; p110α); mammalian target of rapamycin (mTO

Patient sample and mouse studies suggest inhibiting the PI3Kα/mTOR pathway could help treat venous malformations. Genetic sequencing identified activating mutations in PI3KCA in venous malformation lesions from patients, and in patients and a neonatal mouse model of the disease, high PI3KCA levels in epithelial cells correlated with disease progression. In a mouse model of venous malformations induced by an activating PI3KCA mutation, the PI3Kα inhibitor alpelisib decreased venous malformation volume and venous proliferation and increased markers of apoptosis in neutrophils compared with vehicle. In the same model, the mTOR inhibitor Afinitor everolimus decreased venous malformation volume and venous proliferation. In another mouse model of the disease induced by an activating PI3KCA mutation, the generic mTOR inhibitor rapamycin decreased vessel area, disease progression and proliferation of endothelial cells. Next steps include identifying partners for clinical trials in pediatric patients with venous malformations.

Novartis AG markets Afinitor to treat brain, breast and renal cancers; neuroendocrine tumors; heart transplant rejection and renal transplant rejection. Novartis also has the drug approved to treat liver transplant rejection and graft rejection...