mTOR in squamous cell carcinoma of the oesophagus: a potential target for molecular therapy?

Abstract

Aims: The mammalian target of rapamycin (mTOR), an important regulator of protein translation and cell proliferation, is activated in various malignancies. In a randomised controlled trial of advanced renal cell carcinoma patients, targeted therapy to mTOR by means of rapamycin analogues has been shown to significantly improve survival. An in vitro study has revealed that mTOR is activated in oesophageal squamous cell carcinoma (OSCC) cell lines and that mTOR expression is inhibited by rapamycin. The objectives of this histological study were to determine the proportion of OSCC tissues with activated mTOR (p-mTOR) expression, thereby assessing the percentage of patients with OSCC that would possibly benefit from neoadjuvant rapamycin therapy, and to identify the clinicopathological features of these potentially rapamycin-sensitive tumours.

Methods: The expression of p-mTOR (Ser2448) was immunohistochemically assessed in a validated tissue microarray comprising triplicate tissue biopsy cores of 108 formalin-fixed, paraffin-embedded OSCCs. Staining results were correlated with clinicopathological data.

Results: Normal oesophageal epithelium was negative for p-mTOR. Activated mTOR expression was located in the cytoplasm of oesophageal tumour cells. 26 (25%) of 105 assessable OSCCs showed tumour cells with positive staining for activated mTOR. Activated mTOR expression was associated with a lesser degree of differentiation only (p = 0.024). No correlation was detected between p-mTOR and the proliferation marker Ki-67.

Conclusions: Activated mTOR can be detected in one-quarter of OSCCs. Since this subset of patients may potentially benefit from mTOR inhibiting therapy, a phase II clinical trial of neoadjuvant mTOR-inhibiting therapy in patients with OSCC may be considered.