mTOR kinase inhibitors as a treatment strategy in hematological malignancies

The mammalian target of rapamycin (mTOR) kinase is a key element of intracellular signal transduction, responsible for the regulation of cell growth and proliferation. Since abnormal activation of the mTOR pathway was found in several tumors, including human malignancies, it may be an attractive target for antineoplastic treatment. The first identified mTOR inhibitor was rapamycin (sirolimus). Subsequently, the most potent rapamycin analogues (rapalogues), such as everolimus, temsirolimus and deforolimus, have been developed. After encouraging preclinical experiments, several clinical trials testing the rapalogues in monotherapy or in combinations with other cytotoxic agents have been conducted in patients with hematological malignancies. Results of these studies, described in this review, indicate that inhibition of the mTOR pathway may be a very promising strategy of anti-tumor treatment in several types of lymphomas and leukemias. Recently, a second generation of more effective mTOR inhibitors has been developed. These are currently being assessed in preclinical, Phase I or I/II clinical studies.