FTY720 May Treat Imatinib (Gleevec)- Resistant Leukemia

Filed in archive Drugs, Vaccines and Therapeutics on August 28, 2007

In a mouse model, scientists have demonstrated that treatment with a drug known as FTY720 prevents many leukemias caused by the cancer protein BCR-ABL- nearly all cases of blast crisis chronic myeloid leukemia and some cases of acute lymphocytic leukemia. These are fatal leukemias against which Abl kinase inhibitors such as imatinib (Gleevec) fail to induce a long-term response. FTY720 activates protein phosphatase 2A (PP2A), which is a tumor suppressor that is inactivated by signals induced by BCR-ABL.

Our data indicate that FTY720 induces apoptosis and impairs clonogenicity of imatinib/dasatinib-sensitive and -resistant p210/p190BCR/ABL myeloid and lymphoid cell lines and CML-BCCD34+ and Ph1 ALLCD34+/CD19+ progenitors but not of normal CD34+ and CD34+/CD19+ bone marrow cells. Furthermore, pharmacologic doses of FTY720 remarkably suppress in vivo p210/p190BCR/ABL-driven [including p210/p190BCR/ABL (T315I)] leukemogenesis without exerting any toxicity. Altogether, these results highlight the therapeutic relevance of rescuing PP2A tumor suppressor activity in Ph1 leukemias and strongly support the introduction of the PP2A activator FTY720 in the treatment of CML-BC and Ph1 ALL patients.

The pharmacologic doses of FTYY720 used to suppress leukemogenesis in the mice had no adverse effects and FTY720 has thus far shown no adverse effects in clinical trials testing its potential as a therapeutic for the treatment of multiple sclerosis. The study has been published online in the Journal of Clinical Investigation (doi: 10.1172/JCI31095).

Image: A Wright's stained bone marrow aspirate smear of patient with precursor B-cell acute lymphoblastic leukemia. Credit: VashiDonsk