DUAL INHIBITION OF FLT3 AND RET PATHWAYS BY ON150030 AS NOVEL STRATEGY FOR AML THERAPY

  • Ghaffari, Helya (PI)

Project Details

Description

Personnel and Research Development: As a future physician scientist, my career goals involve conducting translational research in oncological sciences. I would like to use my scientific expertise in cancer biology to inspire research projects with the goal of improving cancer therapies and combine this with my clinical experience to provide better care for my cancer patients. My mentor, Dr. E. Premkumar Reddy, is a Professor in the Department of Oncological Sciences and has pioneered the development of small molecule inhibitors against targets in a variety of cancer types. To further expand my knowledge and skill set, I attend departmental and institutional seminars and learn how to use the cutting-edge resources provided by my institution. I also plan on presenting at laboratory, departmental, and national meetings to expand my scientific communication skills.Background and Hypothesis: Approximately one-third of patients suffering from acute myeloid leukemia (AML) harbor a FLT3 Internal tandem duplication mutation (FLT3-ITD). During normal hematopoiesis, FLT3, which is a receptor tyrosine kinase, activates downstream pathways for proliferation. However, when mutated, the kinase loses its auto-inhibitory function, rendering it constitutively active. Clinically, the presence of FLT3-ITD is associated with increased rate of disease relapse. FLT3 inhibitors in current use carry high relapse rates. Quizartinib is a second-generation FLT3 inhibitor that potently induces differentiation in AML, but it only has a median duration of response of 12.1 weeks in FLT3-ITD positive patients. Subsequent studies revealed a secondary mutation in patients who acquired a resistance to Quizartinib (AC220).In this application, we propose to test the utility of ON150030, developed by our group, as a therapeutic agent to treat AMLs. In addition to strongly inhibiting FLT3, ON150030 inhibits RET as well as SRC kinases, which are well known for activating multiple proliferation pathways. In addition, ON150030 binds to the active form of the FLT3 kinase while drugs like Quizartinib bind to the inactive form. Our structural studies suggest that mutations such as D835V are unlikely to affect the inhibitory activity of ON150030 because of its ability to bind to active conformation of the kinase. We hypothesize that combined inhibition of FLT3, RET, and SRC kinases by ON150030 and its unique mode of binding may provide an advantage over FLT3 inhibition alone.Specific Aims:(1) Determine the effects of ON150030 on the signal transduction pathways that are important for growth and viability of AML. Kinase inhibition assays demonstrate that ON150030 very strongly inhibits FLT3 (IC50

StatusFinished
Effective start/end date30/09/1629/09/17

Funding

  • Congressionally Directed Medical Research Programs: $124,612.00

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