Targeting the mTOR/4E-BP Pathway in Endometrial Cancer

Abstract

Endometrial cancer is the most common gynecologic malignancy. Although it is highly treatable in the early stages of disease, therapies for advanced and recurrent disease are rarely curative. A molecular and genetic understanding of endometrial cancer involves the mTOR signaling pathway, an emerging target for treatment of type I disease (the most common presentation). Endometrial cancers show a significant reliance on the mTOR pathway for survival, and studies to date have revealed a clinical advantage in targeting this pathway. Less well developed in the study of endometrial cancer is an understanding of mTOR signaling to its major downstream effector, translational control. Given the poor rate of success for treatment of latestage endometrial cancer, increasing attention is being directed to the development of new therapeutic approaches, including targeting the mTOR pathway. Here, we discuss the potential benefit of targeting mTOR combined with existing chemotherapies by monitoring its impact on translational regulatory pathways and key translation targets in endometrial cancer. We also highlight laboratory and clinical research findings that will provide new avenues for future research and clinical development. Clin Cancer Res; 17(24); 7518-28. Ó2011 AACR.

Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer

“…Understanding this relationship may become particularly important when targeting strategies are designed in the future. 37 We found an inverse relationship between TP53 'mutant'-like expression and loss of ARID1A expression in endometrial cancer and found no loss of ARID1A in non-endometrioid endometrial carcinomas. In ovarian cancer, TP53 mutations were found to be mutually exclusive with ARID1A mutations, 3 and in gastric cancer, a similar inverse relationship was identified.…”

Essential role for autophagy in life span extension

“…In contrast to nutrient starvation, cellular growth signals (along with nutrient opulence) such as receptor binding of IGF-1 suppress autophagy via the activation of Akt, which inhibits the TORC1 repressor TSC1/2 (in addition to a variety of other targets), resulting in the activation of TORC1. Active TORC1 inhibits the autophagy-relevant ULK1 complex ( Figure 2) and in parallel de-represses protein translation via inactivation of S6K and inhibition of the translational repressor translation initiation factor 4E-binding protein 1 (4E-BP1) (10).…”

Inhibition of Endometrial Cancer by n-3 Polyunsaturated Fatty Acids in Preclinical Models

“…Advances in the understanding of the molecular pathology of endometrial carcinoma have lead to the development and testing of targeted therapies (12,13). Of the potential therapeutic targets identified to date, the mTOR signaling pathway is a major target for treatment of this disease (14). mTOR is a highly conserved Ser/Thr kinase that integrates diverse signals, including nutrients, growth factors, energy, and stresses to control cell growth, proliferation, survival, and metabolism (15)(16)(17)(18).…”