Dual PI3K/mTOR Inhibition and Therapeutic Targets in Uterine Sarcoma

Phospho-S6^S240 (p-S6^S240) expression positively correlates with poor prognosis in uterine sarcoma, and PI3K/mTOR inhibition may be an effective strategy for targeting p-S6^S240-expressing disease, according to a study published in Clinical Cancer Research.¹

Uterine sarcoma is a rare but aggressive group of cancers, of which leiomyosarcoma is the most common. PI3K/mTOR signaling is implicated in leiomyosarcoma, though mTOR inhibition was shown to be an ineffective treatment. Prognostic markers and new targets are needed to improve the poor outcomes of these cancers.

For this study, researchers evaluated the expression of 6 potential targets in 288 uterine sarcoma samples, 15 smooth muscle tumors, 52 benign tumors, and 41 normal samples.

Of all 6 evaluated markers, p-S6^S240 expression was linked to inferior progression-free survival, recurrence, and likelihood of being higher-grade for all malignant tumors.

Based on these results, the researchers developed patient-derived xenograft (PDX) models to determine whether dual PI3K/mTOR inhibition would be effective against p-S6^S240-expressing cancers. The models showed that p-S6^S240-expressing tumors would respond to such inhibition with the dual inhibitor, BEZ235.

The authors concluded that p-S6^S240-expression predicts poor prognosis, though sarcomas expressing p- S6^S240 are likely to respond to dual PI3K/mTOR inhibition.

Reference

1. Cuppens T, Annibali D, Coosemans A, et al. Potential targets’ analysis reveals dual PI3K/mTOR pathway inhibition as a promising therapeutic strategy for uterine leiomyosarcomas—an ENITEC Group initiative. Clin Cancer Res. 2017 Feb 23. doi: 10.1158/1078-0432.CCR-16-2149 [Epub ahead of print]