Mammalian target of rapamycin expression in poorly differentiated endocrine carcinoma: clinical and therapeutic future challenges

Abstract

While the mammalian target of rapamycin (mTOR) signaling pathway is a promising target for well-differentiated endocrine carcinoma therapy with the mTOR inhibitor everolimus (RAD001), poorly differentiated endocrine carcinomas (PDECs) are usually excluded from clinical trials due to their aggressiveness. So far, mTOR activity in PDECs has only been tested in cell lines. This study reviewed 36 mono-institutional PDECs to determine mTOR expression. Slides of normal kidney as positive control were used to optimize mTOR staining. To ensure antibody specificity, consecutive sections were incubated in the absence of primary antibody. Immunoreactivity was evaluated on a semi-quantitative scale scoring the extent and intensity of staining. The product of these two scores was used to obtain a total immunostaining score. The main primary site of disease was the pancreas, and 83% of patients had stage IV disease. In 80% of samples, mTOR expression was maintained at similar levels, with no relationship to tumor origin or proliferation rate determined by MIB-1. This study seems to demonstrate that mTOR is expressed in human PDECs regardless of tumor site. Its role in relation to the activity of everolimus in this subset of patients needs to be confirmed.

Antitumor Effect of Everolimus in Preclinical Models of High-Grade Gastroenteropancreatic Neuroendocrine Carcinomas

“…The authors observed a high expression of phospho-mTOR in 67% of PDNECs, as compared to 27% of well-differentiated NETs and carcinomas. Secondly, Catena et al [15] studied the expression of phospho-mTOR in a series of 36 patients diagnosed with PDNECs. A high expression of phospho-mTOR was observed in 80% of these tumors.…”

“…To date, since patients with PDNECs have been excluded from clinical trials, the effects of mTOR inhibitors have not been evaluated in these aggressive tumors. Interestingly, two recent studies have shown that high levels of phospho-mTOR are frequently detected in PDNECs [14,15], which may lend some support to the therapeutic targeting of mTOR pathway in this tumor subset.…”

Predictive factors of response to mTOR inhibitors in neuroendocrine tumours

“…large cell neuroendocrine carcinomas and small cell lung cancers) (Righi et al 2010). Moreover, a strong expression of phospho-mTOR was observed more frequently in poorly differentiated as compared to well differentiated gastroenteropancreatic NETs (Shida et al 2010, Catena et al 2011. Bollard et al (2013) observed a strong expression of the two major mTOR effectors (phospho-p70S6K and phospho-4EBP1) in six human tissue samples of NECs.…”

Neuroendocrine tumors of the digestive system: pathologic and molecular characteristics

“…Информация о значении сигнального пути mTOR в развитии и про-грессии НЭО ЖКТ и ПЖ присутствует в ограничен-ном количестве [75,76]. Вместе с тем активация сиг-нального пути mTOR является одним из ключевых событий, влияющих на рост, пролиферацию, ангиоге-нез и метаболизм нейроэндокринных опухолевых клеток [77][78][79]. В последнее время особое внимание к изуче-нию экспрессии белка mTOR, а также выше-и ниже-лежащих молекул данного сигнального пути связано с появлением препаратов из группы ингибиторов mTOR для лечения НЭН ПЖ и других отделов пище-варительной системы.…”