Acute myeloid leukemia (AML) is the most common type of acute adult leukemia and also accounts for 20% of childhood leukemias. Mainstream treatment of AML consists of intensive chemotherapy regimens with considerable toxicity, and survival rates have remained very low. Clearly, more effective and better tolerated therapies are required. While targeted therapies have received much attention with the success of imatinib for chronic myeloid leukemia, similar therapeutic approaches for other leukemias, including AML, have not produced long-term remissions. FLT3 is a receptor tyrosine kinase (TK) that, once mutationally activated, has been shown to have an important role in leukemogenesis. FLT3 mutations (FLT3MT) occur in about one-third of AML patients and have been associated with a poor prognosis. Small-molecule FLT3 TK inhibitors have shown anti-leukemic activity in clinical trials, although durable responses have not been achieved. RNAi-based synthetic lethal screens have fantastic potential for the identification of pathways that maintain leukemia cell viability i the face of targeted therapies. By using a genome-wide RNAi-based screen, we have identified genes whose suppression is lethal to FLT3MT AML cells in the presence of the FLT3 inhibitor CEP701. We refer to gene products whose inhibition sensitizes AML cells to FLT3 inhibition as 'SLAMs'for Synthetic Lethal in Acute Myeloid leukemia. Multiple components of ATM-dependent pathways were identified as SLAMs. Based on preliminary validation data and the potential for therapeutic targeting, we will focus on ATM-directed metabolic pathway components as promising targets for the development of novel combination therapies to more effectively treat AML.

Public Health Relevance

Acute myeloid leukemia (AML) is the most common leukemia in adults and accounts for 20% of childhood leukemias, and this disease generally fails treatment using conventional chemotherapeutics. Using a large-scale screening approach that examines all known human proteins we have identified several proteins whose suppression is lethal to AML cells in the presence of a FLT3 targeted kinase inhibitor. The goal of this proposal is to use these data to develop novel targeted combination therapies that will greatly improve treatment of patients with AML.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Career Transition Award (K22)
Project #
5K22CA172757-02
Application #
8541799
Study Section
Subcommittee G - Education (NCI)
Program Officer
Wali, Anil
Project Start
2012-09-15
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$135,968
Indirect Cost
$10,072
Name
University of Colorado Denver
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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
Spreafico, Anna; Tentler, John J; Pitts, Todd M et al. (2013) Rational combination of a MEK inhibitor, selumetinib, and the Wnt/calcium pathway modulator, cyclosporin A, in preclinical models of colorectal cancer. Clin Cancer Res 19:4149-62