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.
Project Goal: 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.
Project Update 2022: A protein called Eya1 has important functions in tumor formation and growth in medulloblastoma, a common brain tumor of children. In fact, decreasing the amount of Eya1 have been shown to reduce the number of deaths in mice with these tumors. We developed a compound, DS38, based off a known drug called benzbromarone, that works against EYA proteins. We found that this compound is better at interrupting Eya1 functions than benzbromarone in both mice and human tumors. Our preliminary data suggests that DS38 can increase the life of mice with medulloblastoma tumors. Therefore, our updated results show that this compound can be used to develop a new treatment for pediatric medulloblastoma by interrupting Eya1 functions.
