Endocrine Abstracts

Objective: In vitro data suggest that somatostatin receptors (SSTR) and mTOR pathways might represent reasonable targets for novel therapies, since are involved in growth of adrenocortical carcinoma (ACC). However, in vitro analysis of combination treatments, targeting both mTOR and SSTR as compared to mitotane, and detailed tissue typing mTOR/SSTR pathway are poorly explored in ACC.

Methods: This study was designed to characterize the tissue expression of mTOR/SSTR pathway-related molecules in a series of ACC and to investigate in vitro the effects on growth of SOM230, everolimus and mitotane in ACC cells. Immunohistochemistry for mTOR-related molecules and SSTR subtypes 1 to 5 was performed on a series of 58 ACC and correlated with clinical characteristics. H295R and SW13 ACC cells were incubated with mitotane, SOM230 and everolimus, either alone or in combination. Cell viability was determined by WST-1 method, and drug interactions were calculated using the combination index (CI). Modulation of mTOR and SSTR 1–5 genes was evaluated under treatments using real time PCR.

Results: Heterogeneous profiles of mTOR-related molecules and SSTR expression was observed in ACC samples, with no significant correlations among the different molecules investigated nor with clinical or pathological parameters. In vitro, everolimus determined cytotoxic effects in both ACC cells, with a synergistic effect combining everolimus with either mitotane or SOM230 and with no significant modulation of mTOR gene. By contrast, SOM230 was not effective when used alone in either H295R or SW13 cells, while in combination with mitotane showed an antagonistic effect in SW-13 cells and a synergistic effect in H295R cells (in these latter cells with a significant up-regulation of SSTR genes).

Conclusions: SSTR/mTOR-related molecules are heterogeneously expressed in ACC and multimodal targeting of these pathways – alone or in association with mitotane – might represent an effective treatment in ACC patients to be explored in vivo.