2015 Research Grant
Characterization of CD99 as a Therapeutic Target in MDS and AML.
Conducted by Dr. Stephen Chung at the Memorial Sloan Kettering Cancer Center. Funded in Partnership with the American Society of Hematology.
Acute myeloid leukemia (AML) originates from leukemic stem cells, rare disease-driving cells that have the potential to both renew themselves and propagate other leukemia cells that make up the bulk of AML. Leukemic stem cells are largely resistant to conventional therapies, and they are believed to be the source of residual disease that causes patients to relapse even after they initially respond to therapy. Dr. Chung’s research is aimed at developing a new treatment that has the potential to stop relapse by targeting a specific protein on the surface of leukemic stem cells.
Dr. Chung has found that a protein called CD99 is expressed at greater levels on leukemic stem cells than on normal blood stem cells. It is similarly over-expressed on the stem cells that give rise to another related bone marrow disorder called the myelodysplastic syndromes (MDS.) In his preliminary lab work Dr. Chung has found that monoclonal antibodies targeting CD99 are directly toxic to primary AML and MDS cells, with minimal toxicity to normal blood-forming stem cells. This makes CD99 a promising target for low toxicity therapies that can kill AML and MDS stem cells while leaving normal stem cells alone.
Dr. Chung will now test his innovative approach to see if anti-CD99 monoclonal antibodies can eradicate human AML established in a mouse model by killing off both leukemic stem cells and bulk AML cells.
Dr. Chung will also explore the mechanism by which anti-CD99 drugs can be effective. CD99 regulates the activation of a group of enzymes called the “Src-family kinases,” and he is proposing that the monoclonal antibodies are effective because they cause rapid activation of these kinases, leading to lethal amounts of cellular stress. He will validate this mechanism as a potential novel therapeutic vulnerability in these diseases and identify other CD99-interacting partners or pathways that might also be targeted therapeutically. Finally, Dr. Chung will determine whether CD99 expression can be used as a marker of prognosis and/or minimal residual disease in AML.
The research findings are anticipated to lead to the development of new therapeutics for AML patients directed at CD99, the use of CD99 as a prognostic biomarker, and the identification/validation of pathways associated with CD99 that may also be targeted for therapeutic benefit.
Dr. Stephen Chung