Abstract
Despite the fact that the majority of lymphomas initially respond to treatment, many patients relapse and die from disease that is refractory to current regimens. The need for new treatment strategies in lymphomas has led to the investigation and evaluation of novel agents that target cellular pathways. The mammalian target of rapamycin (mTOR) is a representative pathway that may be implicated in lymphomagenesis. Rapamycin and especially its derivatives (temsirolimus, everolimus, and deforolimus) represent the first described mTOR inhibitors. These agents have shown promising results in the treatment of lymphoid malignancies. On the other hand, new ATP-competitive mTOR inhibitors that provoke a broader inhibition of mTOR activity are in early stages of clinical development. The purpose of this paper is to summarize the existing knowledge about mTOR inhibitors and their use in the treatment of B-cell lymphomas. Relevant issues regarding mTOR biology in general as well as in B-cell lymphoid neoplasms are also discussed in short.
Highlights
Current approaches in treating lymphoid malignancies have focused on the development of therapeutic regimens that selectively target dysregulated signal transduction pathways in neoplastic cells
Among aberrantly activated signaling cascades that are implicated in the pathogenesis of lymphomas is the mammalian target of rapamycin pathway, which is involved in many vital cellular processes [1]
Through the last years it has become clear that mammalian target of rapamycin (mTOR) pathway contributes to the pathogenesis of hematological malignancies by playing a key role in the regulation of many cell functions, such as cell proliferation, cell growth, and angiogenesis
Summary
Current approaches in treating lymphoid malignancies have focused on the development of therapeutic regimens that selectively target dysregulated signal transduction pathways in neoplastic cells. Activity of mTORC1 is regulated by multiple molecular pathways that conduct input generated by growth factors, hormones, cytokines, amino acids, energy, stress- and oxygen-related signals [10,11,12,13]. Among these cascades are the PI3K/Akt (Phosphoinositide 3-kinase/Akt) and Raf/MEK/ ERK (Raf/MEK/extracellular signal-regulated kinase) pathways, which are commonly activated in cancer and may cooperate in malignant transformation [9, 12]. The same malignancyinducing processes may be promoted by abnormally elevated mTORC2 signaling [16, 19,20,21]
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