Targeting symmetric division in pediatric cancers
Most childhood cancers contain tumor cells that are diverse in nature. In an individual patient?s tumor, some cells divide to produce two more dividing tumor cells (symmetric proliferation), resulting in faster tumor growth, while other tumor cells divide and produce one daughter that will divide and one daughter that will not (asymmetric proliferation), resulting in slower tumor growth. We have found that a protein called Eya1 is usually present at high levels in a common brain tumor of children called medulloblastoma, and that Eya1 pushes cells to divide symmetrically. Therefore targeting Eya1 drastically slows tumor growth.
We propose studies to learn how Eya1 works in the tumors, and to develop new small molecule compounds that inhibit the actions of Eya1 in tumors. We already know that Eya1 is an enzyme that removes phosphates from particular proteins. We will use proteomic approaches to identify the specific phosphoproteins that are altered by Eya1, and find out how these proteins work in tumor cells. We have initial compounds that target Eya1, and we are working to understand how they target Eya1 function, so that better drugs may be developed. As Eya1 may also play a role in symmetric proliferation within other pediatric neural tumors, including neuroblastoma, Diffuse Intrinsic Pontine Glioma (DIPG), and medulloblastoma, any drugs developed here are likely to have broad potential in pediatric cancers.