Targeting CTPS1 and nucleotide metabolism in MYC-amplified medulloblastoma
Project Goal: Identify other proteins and pathways required for MYC to function, finding new approaches to specifically eliminate tumor cells.
Institution: Seattle Children’s Research Institute
Researchers: Myron Evans, PhD
Year Awarded: 2023
Type of Childhood Cancer: Medulloblastoma (MB)
Medulloblastoma (MB) is the most common brain tumor in children. One form of MB (G3 MB) commonly has mutations in MYC, a gene which drives aggressive tumor growth. Patients with G3 MB are routinely treated with intense chemotherapy and radiation which commonly leads to devastating side effects that persist into adulthood. Developing therapies that specifically target tumors is therefore a significant unmet need in pediatric cancer. There are no therapies that directly target MYC available for patients today. Instead of going after MYC itself, our lab takes the approach of identifying other proteins and pathways required for MYC to function, finding new approaches to specifically eliminate tumor cells. Preliminary work suggests that an enzyme called CTPS1 is one of these proteins required for tumor growth. We show that targeting CTPS1 causes tumor cells to stop growing but does not actually kill them. We reveal the mechanism behind this survival of tumor cells (activation of a protein called CHK1) and show that combining a drug against CTPS1 and one against CHK1 kills tumor cells in culture and in animal models. In this proposal, we will test a version of the CTPS1 inhibitor that crosses into the brain, an essential step in targeting medulloblastoma. Initial results with this version of the CTPS1 inhibitor combined with our CHK1 antagonist are promising, showing significant killing of tumor cells. We will expand our findings in tumor cells from multiple patients to establish use across patient populations. We will also test our combination in mice that are implanted with human tumors. Completion of this project will validate our combination and support further testing to move it into patients. This project has the potential to bring a new therapeutic option to patients in need and to influence the long term-survival of children suffering from this deadly disease.