2016 Research Grant

Development of Pharmacologic Agents to Target Leukemic Stem Cells. 

Conducted by Dr. Tomasz Cierpicki at the the University of Michigan. Funded in Partnership with The Leukemia & Lymphoma Society.

One of the leading theories as to why most AML treatments fail is that AML is driven by leukemic stem cells that self-renew and propagate the disease. Patients at first will seem to respond to treatment but then relapse because chemotherapy fails to kill the stem cells. Novel drugs that can kill leukemic stem cells are therefore urgently needed. Dr. Cierpicki’s research specifically targets these cells with the development of a potent inhibitor to block the activity of a complex called Ring1B-Bmi1 that leukemic stem cells need for self-renewal.

Dr. Cierpicki’s team has already developed a class of compounds that are able to bind to and inhibit Ring1B-Bmi1 activity –

 an accomplishment that no other labs have reported to date. In the current research, he proposes to develop potent Ring1B-Bmi1 inhibitors optimized with properties that are favorable for use as a drug and that will inhibit leukemia progression, serving as anti-cancer therapies with minimal side effects.

This research is innovative in two ways: its use of novel chemistry and its focus on an epigenetic target in AML stem cells. Unlike conventional chemotherapy, which seeks to kill tumor cells and has severe side effects from the unintentional killing of healthy cells, this epigenetic-based therapy is intended to promote cell differentiation, or the maturation of AML stem cells into normally functioning blood cells. Once mature, the cells would eventually get cleared from the body. The targeted results would be elimination of disease cells without toxic side effects.

The specific aims of the research are to (1) develop potent inhibitors of Ring1B-Bmi1 with optimized drug properties, (2) characterize the mechanism of action of Ring1B-Bmi1 inhibitors in leukemia cell lines, and (3) evaluate the therapeutic potential of targeting Ring1B-Bmi1 using mouse models and patient-derived AML cells. 


The project team has a proven track record of taking novel medicinal chemistry from the lab and launching it on the path to patient treatments. They have developed a type of drug called menin-MLL inhibitors for treatment of certain leukemias and are collaborating with a biotech partner to test this treatment in preclinical studies. Similarly, for the current research, the long-term goal is to advance the inhibitors to preclinical and then clinical trials for acute leukemia patients via collaboration with a biotech company or the LLS Therapy Acceleration Program.



      Dr. Tomasz Cierpicki