The mechanistic target of rapamycin pathway in sarcomas: from biology to therapy

Abstract

Introduction: The mechanistic target of rapamycin (mTOR) is a critical node at the junction of multiple intracellular signaling pathways. Amongst its many functions, mTOR instrumentally coordinates protein synthesis and cell growth in response to varying nutrient levels. The mTOR pathway has been implicated and targeted in several malignancies with modest success. Sarcomas are uncommon but diverse mesenchymal tumors for which systemic therapy is often suboptimal. Unsurprisingly, evidence is accumulating for the relevance of mTOR pathway activation across multiple sarcomas. Several clinical trials testing mTOR targeted therapy in sarcomas recently have yielded mixed results.Areas covered: The biology of the mTOR pathway and its relevance to the maintenance of the cancer phenotype shall be reviewed. The preclinical evidence for mTOR pathway activation in a range of sarcoma subtypes, the pharmacology of current and developing agents targeting mTOR, and results of completed clinical trials in sarcomas will also be discussed. In addition, potential reasons for suboptimal activity and avenues for maximizing therapeutic efficacy of targeting mTOR in sarcomas shall be evaluated.Expert opinion: While little doubt exists that mTOR activation has a role in sarcomagenesis, targeting this pathway with rapalogs has thus far yielded suboptimal results. Beyond the use of next-generation mTOR inhibitors to improve target inhibition, future efforts must focus on rational combinations and establishment of robust biomarkers to enhance therapeutic efficacy.