Dual Inhibition of FLT3 and RET Pathways by ON150030 as Novel Strategy for AML Therapy
Abstract
My career goal is to become a physician-scientist, which is a clinician who dedicates a significant portion of their professional time to doing research. I will use my role as a physician-scientist to be a bridge between the patients and the scientific research behind their disease. With this award, I will be performing research that has a great potential of making a positive impact in the lives of patients suffering from acute myeloid leukemia (AML). I will also learn first-hand about the drug discovery process, which I can later apply to other cancers and other targets implicated in diseases. This way I can use my knowledge to globally improve the care of patients suffering from cancer. Our proposed project, if successful, will reveal new information about the factors that drive AML and understand the precise mechanisms associated with its aggressive growth. Moreover, the drug that we utilize to understand the disease may be a potential novel therapy for AML patients. I have already taken advanced classes that cover an in-depth analysis of cancer and tumor biology, so my researcher development plan involves expanding this expertise specifically into leukemia. By following my plan, I will have sufficient background knowledge to ensure that the results of my project will have an impact on the field, and I will have the skills to be able to articulate my findings with the medical and research community. AML is a very aggressive form of leukemia in which immature cells of the bone marrow grow uncontrollably. Because these cells do not become healthy white and red blood cells, the body ends up deficient in these cells, which are necessary for keeping it in an overall healthy state. There are treatments available for AML that both kill the cancer cells and induce the immature cells to maturity; but even then, the survival rate for AML is low, mainly due to relapse and resistance to the current therapies. There is a great need for a new drug that targets key factors implicated in the disease and has a lasting effect on the disease. Approximately 20%-30% of AML patients harbor an activating mutation in the receptor tyrosine kinase FMS-Like Tyrosine Kinase 3 (FLT3). While present therapies such as Quizartinib induce remission in 40%-50% of patients, there is a high rate of relapse due to mutations at position 835. This finding highlights a need for a new FLT3 inhibitor that will be effective in the Quizartinib-resistant cells, and we propose that ON150030, a drug made and characterized in my mentor s lab, can fill this need. ON150030 binds to the active form of the FLT3 kinase (Type 1) while drugs like Quizartinib bind to the inactive form of the kinase (Type 2). Our structural studies suggest that mutations such as aspartate to valine at position 835 are unlikely to affect the inhibitory activity of ON150030. In addition, ON150030 strongly blocks a few other kinases that are involved in promoting cell replication, most notably RET and SRC kinases. RET is similar to FLT3 in that they both promote growth and proliferation, so by inhibiting both kinases at once, we expect to have higher effect on uncontrolled cell growth. By completely inhibiting two proteins important for the progression of the cancer, we can effectively cause sustained remission of the disease. As with most drugs used in the clinic, there is a risk of the patients developing resistance to ON150030. However, if it is used together with another available drug with a different mechanism of action, the combination can effectively target the entire range of cancerous cells. This will significantly reduce the potential growth of a resistant cell population and virtually cure the patient of disease. The experiments for investigating how ON150030 works molecularly in cancer cells can be completed in a year, and the subsequent studies in mouse models can be completed in the following year. My mentor s laboratory has experience with drug developmen
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610362
Entities
People
- Helya Ghaffari
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army