This proposal will attempt to characterize novel combination therapies for the treatment of chronic myelogenous Leukemia (CML) and other subsets of leukemia. CML is initiated by and dependent on a cancer causing mutation that generates the Bcr-Abl gene. Treatment with inhibitors of the Bcr-Abl enzyme such as Imatinib Mesylate is the current standard clinical practice. While effective in controlling disease in the chronic phase, these inhibitors often fail to eliminate all CML cells and also fail to achieve durable remissions for advanced CML and Bcr-Abl+ acute lymphoblastic leukemias (ALL). Targeting additional gene products in combination with Bcr-Abl inhibitors should be necessary to prevent residual Bcr-Abl+ CML cell survival and achieve durable remissions. An unbiased large-scale genetic screen was performed to identify gene products whose inhibition synergizes with Imatinib Mesylate therapy. This screen identified several pathways including enzymes involved in cellular energy production. This proposal will test the hypothesis that targeting particular metabolic pathways will greatly sensitize CML and Bcr-Abl+ ALL cells to Bcr-Abl inhibition. The goals of this proposal are threefold: 1. To determine whether targeting enzymes involved in energy production in combination with IM cooperates to kill CML cells;2. To determine whether targeting these enzymes in a mouse model of leukemia slows down disease progression;and 3. To determine what are the metabolic consequences of targeting these genes. From a clinical perspective, identifying novel targets that cooperate with Bcr-Abl kinase inhibitors may provide new alternatives for clinical treatments. From a basic science perspective, it will allow us to dissect important pathways utilized by CML cells to overcome treatment with Bcr-Abl inhibitors. Understanding glucose utilization and energy production pathways in cancers is of critical importance to develop metabolic drug therapies. Drugs that can selectively target the altered metabolic profile of tumor cells may sensitize cells to chemotherapy. This proposal will help the National Cancer Institute fulfill their mission to support research projects for the treatment of cancer and to support education and training in fundamental sciences and clinical disciplines relating to cancer.
Chronic myelogenous leukemia cells exhibit altered energy metabolism that allows them to survive inhibition with current clinical therapy. This proposal will attempt to characterize alternative energy pathways utilized by these cells in an attempt to design better metabolic therapies to target these cells.)
|Gregory, Mark A; D'Alessandro, Angelo; Alvarez-Calderon, Francesca et al. (2016) ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia. Proc Natl Acad Sci U S A 113:E6669-E6678|
|Alvarez-Calderon, Francesca; Gregory, Mark A; Pham-Danis, Catherine et al. (2015) Tyrosine kinase inhibition in leukemia induces an altered metabolic state sensitive to mitochondrial perturbations. Clin Cancer Res 21:1360-72|
|Alvarez-Calderon, Francesca; Gregory, Mark A; DeGregori, James (2013) Using functional genomics to overcome therapeutic resistance in hematological malignancies. Immunol Res 55:100-15|
|Christoph, Sandra; Schlegel, Jennifer; Alvarez-Calderon, Francesca et al. (2013) Bioluminescence imaging of leukemia cell lines in vitro and in mouse xenografts: effects of monoclonal and polyclonal cell populations on intensity and kinetics of photon emission. J Hematol Oncol 6:10|