Pharmacological targeting of mammalian target of rapamycin inhibits ovarian granulosa cell tumor growth

Abstract

Few targeted therapies have been developed for ovarian granulosa cell tumor (GCT), even though it represents 5% of all malignant ovarian tumors in women. As misregulation of PI3K/AKT signaling has been implicated in GCT development, we hypothesized that the AKT signaling effector mammalian target of rapamycin (mTOR) may play a role in the pathogenesis of GCT and could represent a therapeutic target. Analyses of human GCT samples showed an increase in protein levels of mTOR and its downstream effectors RPS6KB1, RPS6, eIF4B and PPARG relative to normal granulosa cells, suggestive of an increase in mTOR pathway activity and increased translational activity and/or protein stability. We next sought to evaluate mTOR as a GCT therapeutic target using the Pten (tm1Hwu/tmiHwu);Ctnnb1 (tm1Mmt/+);Amhr2 (tm3(cre)Bhr/+) (PCA) mouse model, in which mTOR, RPS6KB1, eIF4B and PPARG are upregulated in tumor cells in a manner similar to human GCT. Treatment of PCA mice with the mTOR-specific inhibitor everolimus reduced tumor growth rate (1.5-fold; P < 0.05) and also reduced total tumor burden (4.7-fold; P < 0.05) and increased survival rate (78 versus 44% in the vehicle group) in a PCA surgical model of GCT peritoneal carcinomatosis. Everolimus decreased tumor cell proliferation and tumor cell volume relative to controls (P < 0.05), whereas apoptosis was unaffected. Phosphorylation of RPS6KB1 and RPS6 were decreased (P < 0.05) by everolimus, but RPS6KB1, RPS6, eIF4B and PPARG expressions were not affected. These results suggest that mTOR is a valid and clinically useful pharmacological target for the treatment of GCT, although its inhibition does not reverse all consequences of aberrant PI3K/AKT signaling in the PCA model.

Ovarian granulosa cell tumors: a retrospective study of 27 cases and a review of the literature

“…[36] demonstrated an increase in Mtor (mammalian target of rapamycin) deregulation by using a mouse model with granulosa cell tumors. So, targeting Mtor may be beneficial to women with granulosa cell tumors.…”

Stage I granulosa cell tumours: A management conundrum? Results of long-term follow up

“…Furthermore, mammalian target of rapamycin (mTOR) signalling has been shown to be aberrantly activated in some human GCT [43]. Combination therapy with an mTOR inhibitor and a hormonal agent may be of benefit given the potential role of these agents individually in GCT.…”

The Role and Application of Sirtuins and mTOR Signaling in the Control of Ovarian Functions

“…These inhibitors were able to promote apoptosis of human ovarian cancer cells [35,37]; however, these data were not confirmed by other studies [36]. Synthetic mTOR inhibitors failed to affect the apoptosis of healthy mouse [33] and porcine [26] granulosa cells and mouse ovarian granulosa cell tumors [34]. These inhibitors were able to suppress porcine granulosa cells’ progesterone and testosterone output [26].…”

“…The mTOR pathway plays a critical role in the regulation of ovarian cell proliferation, apoptosis, secretory activity, folliculogenesis, and malignant transformation [5,11,26,31,32,33,34,35,36,37,38,39,40,41,42,43,44]. The mTOR and SIRTs are in close mutual functional interrelationships.…”