The long-term objective of this application is the discovery of small molecule therapies for acute myelogenous leukemia (AML). Therapies that target the underlying molecular causes of cancer represent a new frontier in cancer chemotherapy. At present, only a small number of targeted therapies have been successfully developed, primarily because molecular targets capable of reversing disease progression are difficult to identify. Nevertheless, even when valid therapeutic targets have not been identified, it may still be possible to discover targeted therapies by high-throughput screening for small molecules that promote phenotypic rescue in an appropriate disease model. AML is the most common type of leukemia and is frequently caused by the chromosomal translocation product, AML1-ETO. We have developed a transgenic zebrafish model of AML by expressing human AML1- ETO from an inducible promoter in zebrafish. Induction of AML1-ETO expression in zebrafish produces a reproducible phenotype that exhibits many of the hallmarks of AML. This AML1-ETO phenotype can be detected readily in the intact zebrafish embryo by a variety of automated screening techniques. Using this unique model of AML, we propose to develop assays for automated, high-throughput screens that can be used to identify therapeutic targets and small molecules capable of reversing the oncogenic effects of AML1- ETO expression. We propose to: 1) Test the effects of perturbing putative AML1-ETO effectors on the zebrafish AML1-ETO phenotype. 2) Develop automated assays for detecting suppression of the AML1-ETO phenotype in intact zebrafish. 3) Validate the AML1-ETO assays with pilot screens of 2000 small molecules with known bioactivities. Because zebrafish allow small molecule screening to be performed in an intact vertebrate organism, the proposed assays have the potential to discover small molecules that function through a variety of novel mechanisms, and hits are selected not only for efficacy but also for suitable ADME/toxicity properties. Therefore, the assays are innovative in that they combine the scale and throughput of high-throughput screens with the physiological relevance of testing in animal models. Relevance - This application proposes to develop simple, robust assays that will allow thousands of chemical compounds to be tested for their ability to reverse the effects of a leukemia-causing genetic defect. Compounds discovered using these tests will provide important insights into how this cancer progresses and may be useful tools for treating leukemia. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA118498-02
Application #
7167738
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Song, Min-Kyung H
Project Start
2006-01-09
Project End
2008-12-31
Budget Start
2006-12-31
Budget End
2007-12-31
Support Year
2
Fiscal Year
2007
Total Cost
$223,027
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Yeh, Jing-Ruey J; Munson, Kathleen M; Elagib, Kamaleldin E et al. (2009) Discovering chemical modifiers of oncogene-regulated hematopoietic differentiation. Nat Chem Biol 5:236-43
Yu, Paul B; Hong, Charles C; Sachidanandan, Chetana et al. (2008) Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol 4:33-41
Kokel, David; Peterson, Randall T (2008) Chemobehavioural phenomics and behaviour-based psychiatric drug discovery in the zebrafish. Brief Funct Genomic Proteomic 7:483-90
Dayyani, Farshid; Wang, Jianfeng; Yeh, Jing-Ruey J et al. (2008) Loss of TLE1 and TLE4 from the del(9q) commonly deleted region in AML cooperates with AML1-ETO to affect myeloid cell proliferation and survival. Blood 111:4338-47