Our long-term goals are to increase the cure rate and decrease chemotherapy-relate toxicity for patients with leukemia. In particular, we are interested in patients whose leukemias express an activated FLT3 receptor, either as a result of mutation or ligand co-expression. 20% of AML patients have mutations of the FLT3 receptor. These patients have a particularly poor prognosis with almost no one being cured in either the pediatric or adult populations. The mutation of the FLT3 receptor consists of small (18-105 bp) internal tandem duplications (ITDs) which are unique for each patient but all map to the juxtamembrane region of the receptor. These mutations constitutively activate the tyrosine kinase domain of FLT3 receptor which is required for signaling. This makes the development of novel strategies for these patients imperative if we are to effect improvements in their outcome. If FLT3 constitutive activation is contributing to leukemogenesis in these patients, one strategy would be to develop small molecule inhibitors of the kinase domain of the receptor. We therefore propose two major specific aims in this proposal with FLT3 as the novel molecular target for drug discovery. The first id to validate FLT3 as a molecular target by developing several animal models that mimic different ways that the FLT3 can become constitutively activated. We will also introduce second """"""""hits"""""""" that often occur in leukemia to study the spectrum of the hematopoietic disease to which an activated FLT3 can contribute.
The second aim i s to develop assays utilizing cell lines and proteins that can be utilized for high-throughout screening of FLT3 inhibitors. This will enable the discovery of lead compounds that are unable to inhibit FLT3 in a highly potent and specific fashion. We believe that this work will lead to the identification of compounds able to inhibit FLT3 which will ultimately be used as novel therapeutics against leukemia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA091177-04
Application #
6756426
Study Section
Special Emphasis Panel (ZCA1-SRRB-D (J3))
Program Officer
Forry, Suzanne L
Project Start
2001-06-01
Project End
2005-05-31
Budget Start
2004-07-06
Budget End
2005-05-31
Support Year
4
Fiscal Year
2004
Total Cost
$353,997
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Ma, Hayley S; Nguyen, Bao; Duffield, Amy S et al. (2014) FLT3 kinase inhibitor TTT-3002 overcomes both activating and drug resistance mutations in FLT3 in acute myeloid leukemia. Cancer Res 74:5206-17
Baldwin, B R; Li, L; Tse, K-F et al. (2007) Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease. Leukemia 21:764-71
Brown, Patrick; Levis, Mark; Shurtleff, Sheila et al. (2005) FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression. Blood 105:812-20
Chen, Peili; Levis, Mark; Brown, Patrick et al. (2005) FLT3/ITD mutation signaling includes suppression of SHP-1. J Biol Chem 280:5361-9
Whartenby, Katharine A; Calabresi, Peter A; McCadden, Erin et al. (2005) Inhibition of FLT3 signaling targets DCs to ameliorate autoimmune disease. Proc Natl Acad Sci U S A 102:16741-6
Brown, Patrick; Meshinchi, Soheil; Levis, Mark et al. (2004) Pediatric AML primary samples with FLT3/ITD mutations are preferentially killed by FLT3 inhibition. Blood 104:1841-9
Levis, Mark; Small, Donald (2004) Small molecule FLT3 tyrosine kinase inhibitors. Curr Pharm Des 10:1183-93
Smith, B Douglas; Levis, Mark; Beran, Miloslav et al. (2004) Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 103:3669-76
Zheng, Rui; Levis, Mark; Piloto, Obdulio et al. (2004) FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood 103:267-74
Zheng, Rui; Klang, Kendra; Gorin, Norbert C et al. (2004) Lack of KIT or FMS internal tandem duplications but co-expression with ligands in AML. Leuk Res 28:121-6

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