Development of Targeted Leukemia Inhibitors Using Nanoparticle Delivery

Background
Acute myeloid leukemia is the most frequent myeloid neoplasia in pediatric cancers, and it develops from the accumulation of mutations in the blood stem cells in the bone marrow. A recurrent mutations is the chromosome inversion inv16(p13q22), which creates the fusion protein CBFbeta-SMMHC. This fusion plays an important role in the expansion and survival of the leukemic cells.

Project Goal
Our laboratory has developed a small molecule that inactivates the fusion protein, and kills the leukemic cells but not normal cells. However, the limited solubility of the small molecule in aqueous solutions, like in serum, limits its use in mice and patients. Here, we propose to combine the chemistry concept of "poly-valency" and nanotechnology to increase the solubility and activity of the small molecule in leukemic cells. We also propose to evaluate its ability to eliminate leukemic cells in a mouse model for CBFbeta-SMMHC AML. In summary, the proposed studies will combine chemistry, nanotechnology and molecular biology concepts for the development of a new and effective targeted therapy for inv16 acute myeloid leukemia.