Current management approaches are limited and may not address the underlying cause of disease
To date, there are no approved therapies for PROS (PIK3CA-Related Overgrowth Spectrum) that aim to affect its root cause: PIK3CA mutation.
Surgical and radiologic embolization procedures are currently the most common approaches to managing PROS. These procedures, however, may be unsuitable for some patients based on the risk-benefit profile.1-4
Nonetheless, surgery is common in childhood. Patients, however, may experience recurrence following surgery, and repeat surgeries are frequently required.1,2,5 In one study of 35 patients (median age, 7 years), 83% had undergone surgery, with more than half requiring multiple surgeries.2
There is a need for treatment options that diminish overgrowth, reduce symptoms, and improve quality of life.2,5,6
Investigational approaches look to address the root cause of PROS
The potential for PI3K inhibition to affect the root cause of PROS provides a rationale for research into this therapeutic approach.
In preclinical murine models of PIK3CA mutation-induced vascular malformations, PI3K inhibition reduced vascular malformation volume, reduced proliferation, and increased apoptosis. However, the clinical significance has not been established. Ongoing clinical research is clarifying the potential role of PI3K inihibition for patients across the spectrum of PROS disorders.1,7
- Madsen RR, Vanhaesebroeck B, Semple RK. Cancer-associated PIK3CA mutations in overgrowth disorders. Trends Mol Med. 2018;24(10):856-870.
- Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, et al. Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am J Med Genet A. 2014;164A(7):1713-1733.
- Keppler-Noreuil KM, Lozier J, Oden N, et al. Thrombosis risk factors in PIK3CA-related overgrowth spectrum and Proteus syndrome. Am J Med Genet C Semin Med Genet. 2019;181(4):571-581.
- Bessis D, Vernhet H, Bigorre M, Quere I, Rossler J. Life-threatening cutaneous bleeding in childhood Klippel-Trenaunay syndrome treated with oral sirolimus. JAMA Dermatol. 2016;152(9):1058-1059.
- Crunkhorn S. Nat Rev Drug Discov. 2018;17(8):545.
- Venot Q, Blanc T, Rabia SH, et al. Nature. 2018;558(7711):540-546.
- Castel P, Carmona FJ, Grego-Bessa J, et al. Somatic PIK3CA mutations as a driver of sporadic venous malformations. Sci Transl Med. 2016;8(332):332ra42.