Alex's Lemonade Stand Foundation for Childhood Cancer

Pascal Duijf

Project Overview

The past decades have witnessed major progress in the treatment of childhood cancers. However, the development of more effective therapy is delayed by our limited understanding of how these cancers develop. The p53 gene is mutated in many human cancers, including some of the types with the poorest survival rates in children, such as blood, brain and connective tissue cancers. Chromosomal abnormalities and excessively high levels of a protein called Mad2, which ensures that the chromosomes of cells are accurately segregated during cell division, are also common in childhood tumors. However, it is unknown to what extent these abnormalities are linked. I recently discovered that p53 prevents high levels of Mad2, which in turn prevents chromosomal abnormalities and tumor development. I propose to study the underlying molecular mechanism in more detail. This may open up new avenues for drug discovery to treat various types of childhood cancer. I will also use mice that develop tumors to see whether normalizing high levels of Mad2 reduces chromosomal abnormalities and tumor size. Finally, I will use childhood tumor samples that have been surgically removed from patients to see whether disrupted p53 function, high Mad2 levels and chromosomal abnormalities also correlate in human childhood tumors. Because efforts to restore p53 function directly in human tumors have only shown limited success, preventing abnormalities secondary to p53 malfunction may become an attractive alternative. Therefore, results from the experiments proposed here may ultimately contribute to developing more effective treatment for a broad range of cancers in children.