PI3K/Akt/mTOR Pathway in Acute Lymphoblastic Leukemia Targeted Therapies

Acute Lymphoblastic leukemia (ALL) comprises a subset of different hematologic neoplasms characterized by impaired proliferation of immature lymphoid cells in bone marrow and peripheral blood. Pediatric patients have experienced treatment success with 5- year overall survival rates approaching 90%, whereas ALL adult patients are associated with poorer survival. Therefore, the development of new targeted therapeutic protocols constitutes a primary need. Phosphoinositide 3-kinases (PI3Ks) and their downstream mediators Akt and mammalian target of rapamycin (mTOR) represent the main components of the PI3K/Akt/mTOR signaling network. It is a key regulatory signaling cascade which drives proliferation, survival and drugresistance of cancer cells, and it is frequently up-regulated in the different T- and BALL subtypes. Serious and irreversible late effects from conventional therapy are a growing issue for leukemia survivors, both for adult and pediatric patients. Therefore, the need to develop targeted and personalized therapy protocols for the treatment of leukemias is mandatory. Recent diagnostic tools allow to design therapeutic protocols with increased target specificity towards PI3K/Akt/mTOR axis that represents a critical target for cancer therapy. This chapter will focus on how this pathway could constitute a paradigm for the development of therapeutic strategies and how effective the recent pharmacological Small Molecule Inhibitors (SMIs) can suppress leukemic cell growth.

Keywords: Acute Lymphoblastic Leukemia, Apoptosis, Autophagy, Cytotoxicity, PI3K/Akt/mTOR, Proliferation, Signal transduction, Small Molecule Inhibitors (SMIs), Survival, Targeted Therapies, Tyrosine Kinase Inhibitors (TKIs).