|Education||BS, Western Washington University|
|Current Position||Postdoctoral Fellow|
Johns Hopkins University
Characterization of a novel FLT3 tyrosine kinsase inhibitor in AML
Acute myeloid leukemia (AML) is a hematologic malignancy ocurring globally in 200,000 people each year. It is characterized by myeloproliferation and a block in cellular differentiation, leading to infiltration of immature blasts in the bone marrow and peripheral blood. FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase expressed in hematopoetic progenitor cells. Approximately 30% of AML cases harbor a mutation in the FLT3 gene leading to constitutive activation of FLT3, which provides a survival and proliferatice advantage to cells. Mutations in FLT3 confer a poor prognosis, and many studies are directed at developing and testing novel FLT3 inhibitors for the treatment of AML.
My project is focused on the characterization of a novel tyrosine kinase inhibitor (TKI) that we hypothesize possesses potent activity against FLT3. I will be working with a panel of AML cell lines, human AML patient samples, and transgenic and xenograft mouse models of AML in order to determine the scope of this compound’s potential application in the treatment of AML patients with FLT3 activating mutations. We are particularly interested in changes in cell viability and signal transduction upon treatment with the inhibitor, as well as perturbation of tumor growth in mice. We are also hoping that these studies will allow us to gain further insight into the development of drug resistance to TKIs, which has been frequently observed with other FLT3 inhibitors in clinical trials. With this information, we can propose combination therapies that will target additional pathways in order to increase the success rate of treatment.
Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Galanis A, Ma H, Rajkhowa T, Ramachandran A, Small D, Cortes J, Levis M. Blood. 2014 Jan 2;123(1):94-100. doi: 10.1182/blood-2013-10-529313. Epub 2013 Nov 13. PMID:24227820
TTT-3002 is a novel FLT3 tyrosine kinase inhibitor with activity against FLT3-associated leukemias in vitro and in vivo. Ma H, Nguyen B, Li L, Greenblatt S, Williams A, Zhao M, Levis M, Rudek M, Duffield A, Small D. Blood. 2014 Mar 6;123(10):1525-34. doi: 10.1182/blood-2013-08-523035. Epub 2014 Jan 9. PMID:24408321
FLT3 kinase inhibitor TTT-3002 overcomes both activating and drug resistance mutations in FLT3 in acute myeloid leukemia. Ma HS, Nguyen B, Duffield AS, Li L, Galanis A, Williams AB, Brown PA, Levis MJ, Leahy DJ, Small D. Cancer Res. 2014 Sep 15;74(18):5206-17. doi: 10.1158/0008-5472.CAN-14-1028. Epub 2014 Jul 24. PMID:25060518
Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia. Lim Y, Gondek L, Li L, Wang Q, Ma H, Chang E, Huso DL, Foerster S, Marchionni L, McGovern K, Watkins DN, Peacock CD, Levis M, Smith BD, Merchant AA, Small D, Matsui W. Sci Transl Med. 2015 Jun 10;7(291):291ra96. doi: 10.1126/scitranslmed.aaa5731. Erratum in: Sci Transl Med. 2015 Jul 8;7(295):295er6. Ma, Haley [corrected to Ma, Hayley]. PMID:26062848