An Intersection of Cell Metabolism and Differentiation in Childhood Sarcomas

Background
The goal of our proposal is to identify new therapeutic targets for one of the most aggressive childhood sarcomas - malignant rhabdoid tumors. These dreadful tumors typically strike infants and young children. Chemotherapy and radiation are rarely curative and no other effective treatment is currently available. As a result, the majority of children with this type of tumor expire within the first year of diagnosis.

It is well established that most childhood sarcomas have defects in mesenchymal cell differentiation. Thus, therapies that target and correct these defects and induce terminal differentiation in sarcomas are an attractive alternative to chemotherapy and radiation. Differentiation therapies have shown great success in the treatment of leukemias and are beginning to be used in clinical trials for the treatment of solid tumors, including sarcomas.  Because of the rarity of rhabdoid tumors, it is difficult to conduct clinical trials to assess the efficacy of differentiation therapies in this tumor type.

Project Goal
Our studies in a mouse model demonstrate that it is possible to induce differentiation of this tumor into bone by altering cell metabolism. This discovery presents an opportunity to exploit cell metabolism for differentiation therapy. Several drugs that target metabolism are already in clinical trials for various diseases but have not yet been tested in rhabdoid tumors. We will test these drugs for their efficacy to induce bone differentiation in mouse models of rhabdoid tumors. Our preclinical studies will facilitate the development of human clinical trials and contribute to saving children's lives in the future.