High-risk medulloblastoma is a devastating childhood brain cancer that results in death in nearly 50% of patients. To improve future treatments for this disease, Dr. Prensner is studying a category of newly-discovered "dark proteins", which have been excluded from prior work due to their small size and unconventional locations in the human genome. He has found that a group of these dark proteins are critical for medulloblastoma cells to survive. This research will reveal how these dark proteins may point toward new approaches to treat medulloblastoma, which may be critical to define the next generation of anti-cancer therapies in this disease. This grant was awarded at Dana Farber Cancer Institute and transferred to the University of Michigan.

Dr. Sykes is developing new therapies for childhood leukemia and lymphoma. Specifically, he is looking at a type of leukemia that develops from abnormal T-cells and is named acute lymphoblastic leukemia (T-ALL). T ALL is a particularly deadly disease if it does not respond to therapy (refractory) or if it responds initially and then comes back (relapsed). When a normal T cell becomes a leukemia cell, it develops certain advantages and certain disadvantages. Therefore, one way to kill a leukemia cell is to identify these disadvantages and to exploit those using specific drugs. This research focuses on how leukemia cells make DNA and RNA building blocks called nucleotides. An enzyme called DHODH is essential to the process of making nucleotides within the leukemia cell. Drugs that inhibit this enzyme rapidly kill the leukemia cells and spare the life of normal cells. Researchers call this approach 'nucleotide starvation' because it starves the leukemia cells of these DNA and RNA building blocks. Normal cells have back-up systems to deal with periods of nucleotide starvation. Dr. Sykes believes that leukemia cells have lost these back-up systems and that is why they are so sensitive to starvation. So far his research has shown that this nucleotide starvation approach works extremely well in leukemia cells outside of the body and in leukemia cells in laboratory mouse leukemia models. The fact that many DHODH inhibitor drugs are already available and have already been tested in humans suggests that clinical trials are feasible and could begin in a timely manner. Dr. Sykes hopes that DHODH inhibitor therapy will be effective treatment for children with T ALL, especially those children who have run out of other good treatment options.

Based on progress to date, Dr. Ou was awarded a new grant in 2022 and 2023 to fund an additional year of this Scholar grant. Due to the tumor and treatment damaging the developing brain, 60-80% of pediatric brain tumor survivors experience long-term neurocognitive impairment. There are two possible paths to improve outcomes: intervene the adverse brain development after treatment, or further optimize radiotherapy dose distribution in the brain before treatment. For the former, the question is to find at-risk patients to intervene after treatment. For the latter, the question is to find target brain regions, where changing radiation doses can potentially change outcomes. Both questions have been studied on the population-level, not on the individual level. This project aims to push our knowledge in these two fronts to the individual level. Dr. Ou is using data from 3 just finished clinical trials to find target patients and find target brain regions for radiation dose optimization. Compared to studies that consider one risk factor a time, Dr. Ou will consider a comprehensive set of risk factors to improve precision to the individual level. The results will allow him to design future larger-scale, multi-site retrospective replicative and eventually prospective clinical trials, to improve neurocognitive outcomes in this vulnerable population before and after treatment.

This grant is generously supported by the Grace for Good Fund, established in honor of Grace Carey and celebrates her survivorship from medulloblastoma. Her cancer journey began in 2007 when she was diagnosed at age 5 with a treatment regime that entailed surgery, proton beam therapy and chemotherapy. While Grace handled it all with minor setbacks, she now faces the physical, emotional and cognitive challenges wrought by the very medications and procedures that saved her life. This fund was inspired by Grace’s desire to help other kids with cancer and supports research of brain tumors and the multitude of challenges facing survivors post treatment.