Widening the therapeutic index for pediatric medulloblastoma by targeting BET proteins
Treatment of human cancers with chemotherapy or radiation with curative intent has led to the successful eradication of tumors in millions of patients, yet the cell death induced in healthy tissues drastically limits their use. This is especially true for pediatric cancer patients, who frequently experience higher cure rates than adults but, unfortunately, also higher rates of treatment-induced toxicities and long-term adverse health effects. For example, external beam radiation therapy (xRT) is a commonly-used treatment modality for brain tumors across patients of varying ages but the risk of developing severe and life-long neurocognitive impairment (NI) is highest in young children. Importantly, these outcomes are not rare, with cancer-related cognitive dysfunction affecting over 115,000 childhood cancer survivors in the US. xRT is less toxic to older children and adults yet the basis for this difference in sensitivity was previously unknown. Our proposal seeks to leverage our recent discoveries and cutting-edge approaches to shed new light on the toxicities caused by cancer therapies in young patients. We will also build our understanding of how cell death pathways are regulated in pediatric brain tumor cells in order to design therapies that can achieve higher cure rates while causing no harmful side effects.
Project Goal
Children diagnosed with medulloblastoma (MB) can often be cured with surgery, radiation, and chemotherapy. However, these treatments can cause lifelong brain function impairment, particularly in the youngest patients. Our lab is dedicated to developing better treatments for pediatric cancer patients by widening the therapeutic index: increasing tumor sensitivity to therapy while reducing toxicities. We have recently made a discovery that may allow us to accomplish this for MB patients: we found that brain cells in young children are poised to undergo a form of cell death called apoptosis, which makes these cells hypersensitive to radiation therapy and chemotherapy. This sensitivity is due to high expression levels of a protein called BAX, which is necessary for apoptosis in response to radiation therapy in brain cells. Importantly, we found that we could reduce BAX levels in normal brain cells by blocking the activity of the protein Myc, which protects neurons from radiation therapy. Interestingly, Myc is highly overexpressed in medulloblastoma cells, and these tumor cells are addicted to this growth-promoting protein. Excitingly, when we inhibit this protein in medulloblastoma cells, most cells immediately die and those that are remaining become even more sensitive to radiation therapy. Our study aims to optimize use of indirect Myc inhibitors to improve medulloblastoma treatment outcomes by maximizing tumor responses and cure rates while minimizing neurotoxicity.
