Cancer is the leading cause of disease-related deaths among children 1 to 14 years of age, and leukemia is the most common malignancy in children. Every year, approximately 20% of children diagnosed with acute leukemia are diagnosed with acute myelogenous leukemia (AML). Though AML constitutes a smaller percentage of childhood leukemia than acute lymphoblastic leukemia (ALL), AML carries an inferior prognosis. In contrast to the improvements in ALL cure rates over the past 20-30 years (now ~80% overall survival), the overall survival for pediatric AML is 50-60% and the chemotherapy is intensive with frequent required hospitalization. Relapsed AML carries survival rate with chemotherapy alone of 20% to 30%. This suboptimal prognosis demonstrates the need for more research into improvement in the outcome of pediatric AML. Furthermore, current chemotherapeutics produce significant short-term and long-term toxicities. Thus, new therapies are needed to continue to improve efficacy and decrease treatment related toxicity. My lab studies Mer and Axl, receptor tyrosine kinase proteins abnormally expressed and activated in childhood acute myeloid leukemia. Mer and Axl have multiple functions pertaining to cell cycling, survival, and proliferation. In the current grant proposal, we will evaluate leukemia cell death after inhibition of Mer and/or Axl in childhood myeloid leukemia cells using novel biologic inhibitors developed in my lab. We will also provide additional evidence in cell culture for our exciting preliminary results that Mer inhibition makes leukemia cells more sensitive to standard leukemia chemotherapy drugs. Additionally, Mer and inhibition will be tested for efficacy in mouse animal models of human leukemia. These experiments will help establish the related Mer and Axl receptors as novel targets for childhood AML therapy. The proposed studies will also potentially provide pediatric oncologists with a highly effective and much less toxic alternative to the currently used chemotherapy drugs in the treatment of childhood AML.

Public Health Relevance

Significant advances have been made in cancer therapy for pediatric leukemia;however, future improvements will likely rely on the discovery of new agents to improve outcome and decrease the adverse side effects associated with the currently used chemotherapy drugs. My research lab has identified abnormal expression of two proteins that may contribute to the development of pediatric myeloid leukemia. We propose to test inhibitors we have developed which kill leukemia cells expressing these abnormal proteins, leading to potential new therapies for pediatric leukemia which would cause less toxicity than the currently used chemotherapy drugs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA137078-03
Application #
8267692
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Arya, Suresh
Project Start
2010-08-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$297,284
Indirect Cost
$96,009
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Zhang, Weihe; DeRyckere, Deborah; Hunter, Debra et al. (2014) UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor. J Med Chem 57:7031-41
Schlegel, Jennifer; Sambade, Maria J; Sather, Susan et al. (2013) MERTK receptor tyrosine kinase is a therapeutic target in melanoma. J Clin Invest 123:2257-67
Lee-Sherick, A B; Eisenman, K M; Sather, S et al. (2013) Aberrant Mer receptor tyrosine kinase expression contributes to leukemogenesis in acute myeloid leukemia. Oncogene 32:5359-68
Linger, R M A; Cohen, R A; Cummings, C T et al. (2013) Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer. Oncogene 32:3420-31
Christoph, Sandra; Deryckere, Deborah; Schlegel, Jennifer et al. (2013) UNC569, a novel small-molecule mer inhibitor with efficacy against acute lymphoblastic leukemia in vitro and in vivo. Mol Cancer Ther 12:2367-77
Linger, Rachel M A; Lee-Sherick, Alisa B; DeRyckere, Deborah et al. (2013) Mer receptor tyrosine kinase is a therapeutic target in pre-B-cell acute lymphoblastic leukemia. Blood 122:1599-609
Christoph, Sandra; Lee-Sherick, Alisa B; Sather, Susan et al. (2013) Pre-clinical evaluation of tyrosine kinase inhibitors for treatment of acute leukemia. J Vis Exp :e50720
Cummings, Christopher T; Deryckere, Deborah; Earp, H Shelton et al. (2013) Molecular pathways: MERTK signaling in cancer. Clin Cancer Res 19:5275-80
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
Migdall-Wilson, Justine; Bates, Christine; Schlegel, Jennifer et al. (2012) Prolonged exposure to a Mer ligand in leukemia: Gas6 favors expression of a partial Mer glycoform and reveals a novel role for Mer in the nucleus. PLoS One 7:e31635

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