Enhancing the effectiveness of nucleoside analogs with mTORC1 blockers to treat acute myeloid leukemia patients

Despite continuous advances in the knowledge of the biology of acute myeloid leukemia (AML), the prognosis of AML patients treated with standard chemotherapy is still poor, especially in the elderly (> 60 y). It should be considered that AML mainly develops in the elderly, with a median age at diagnosis of 68 y and a growing incidence over 65 y. AML accounts for about 25% of all adult leukemias in the western world, and it is the second most frequent form of leukemia following chronic lymphocytic leukemia. Given the extremely poor prognosis of AML, there is a need for novel targeted and less toxic therapies, especially for patients who are over 60 y or those who develop resistance to traditional chemotherapeutic drugs. Constitutively active phosphatidylinositol 3-kinase (PI3K)/ Akt/mammalian target of rapamycin (mTOR) signaling is a common feature of AML patients, where it negatively influences response to therapeutic treatments. A major issue in the efforts to treat AML patients is the inability of current therapies to efficiently target and eradicate leukemia initiating cells (LICs), which are the cells thought to initiate and maintain the leukemic phenotype. In a recent, open-label phase II trial performed by the Italian GIMEMA cooperative group, the efficacy and safety of the drug combination consisting of low-dosage clofarabine with the allosteric mTOR complex 1 (mTORC1) inhibitor temsirolimus (CCI779, Torisel) was studied in a group of elderly patients with refractory/relapsed AML. Some encouraging clinical results Enhancing the effectiveness of nucleoside analogs with mTORC1 blockers to treat acute myeloid leukemia patients