Targeting the PI3K Pathway in Gynecologic Malignancies
This review explores the PI3K pathway aberrations common in gynecologic malignancies, the relevant therapeutic targets that have been explored to date particularly given their success in endometrial cancers, and predictive biomarkers of response to therapy. Landmark trials have been noted involving this pathway, particularly in endometrial cancers. One phase II trial of the potent orally bioavailable mTOR inhibitor, everolimus, in combination with letrozole demonstrated an unprecedented clinical benefit rate (CBR) of 40% and high objective response rate (RR) of 32% in hormone agnostic endometrial cancers. This was followed by GOG 3007 that compared everolimus and letrozole to hormonal therapy yielding similar response rates but double progression-free survival rates. The phosphoinositide 3-kinase (PI3K) signaling pathway is implicated in tumorigenesis given its regulation over cell growth, cellular trafficking, and angiogenesis. In gynecologic malignancies, alterations in PI3K signaling are common. Therefore, developing modulators of the PI3K pathway and identifying molecular markers to predict response are of great interest for these cancer types.