Leukemia is the result of the altered function of proteins that normally regulate the growth of blood cells. In particular, chronic myelogenous leukemia (CML) is a biphasic disease caused by the deregulated activity of a protein known as BCR/ABL. The use of Imatinib (Gleevec; STI571), the first rationally designed anticancer drug that inhibits the activity of BCR/ABL, is favorable for improving the treatment of patients with CML in stable phase. However, imatinib does not prevent the relapse of the disease in its acute phase (blast crisis) and is not effective in killing CML cells bearing a mutated BCR/ABL and the most primitive CML stem cell. Likewise, the recently discovered dasatinib (BMS-354825) is also not effective in the treatment of CML blast crisis patients, and it does not target the primitive CML stem cells. Thus, further investigation aimed at understanding the mechanisms whereby the oncoprotein BCR/ABL abnormally regulates the growth of blood cells is required for the discovery of new potential therapeutic targets.

The ability of BCR/ABL to induce CML and contribute to progression of the disease into its acute phases depends on its deregulated enzymatic activity, which leads to inactivation of factors that suppress tumor development and progression. We recently found that the activity of one of these tumor suppressors, a cellular enzyme called PP2A, is markedly inhibited by BCR/ABL specifically in CML patients in blast crisis. Interestingly, in imatinib-sensitive and -resistant cells as well as in primary marrow cells of CML blast crisis patients, activation of PP2A inhibits BCR/ABL expression (including the imatinib-resistant T315I BCR/ABL) and its ability to induce a fatal leukemia in animals. Thus, the main objective of this study is to investigate whether pharmacological PP2A activation prevents disease progression and efficiently induces killing of the CML stem cell. Furthermore, the investigation of the mechanisms leading to PP2A inactivation in blast crisis CML may lead to identification of factors that if pharmacologically targeted will prevent inactivation of the tumor suppressor activity of the PP2A enzyme. The approaches that we will undertake to successfully bring to completion the proposed experimental tasks relies on the use of the most advanced and gold-standard molecular techniques available for these type of studies, mouse models of CML, CML cells from patients in the stable and acute phases of the disease and BCR/ABL+ cell lines. Indeed, we already have successfully tested the in vivo anti-leukemic activity and safety of two PP2A-activating drugs that have been and/or are currently used in clinical trials for other diseases and are therefore potentially available for treatment of CML patients.

Thus, the successful completion of these studies will provide oncologists with new tools capable of (a) increasing remission-rate of blast crisis CML patients, (b) preventing progression of the disease in those CML patients that become refractory to imatinib therapy, and, perhaps, (c) eradicating the disease at the stem cell level.