Overcoming Resistance in High Risk Medulloblastoma

Brain tumors are the leading cause of death from cancer in children, and medulloblastoma is the most common type of malignant brain cancer. Patients with high-risk medulloblastoma are particularly resistant to the treatments that currently exist. When children with medulloblastoma are resistant to therapies, they have very few options for treatment and long-term survival tends to be poor. More effective therapeutic options for treatment-resistant cancers are crucial.

A team of international researchers led by William Weiss, MD, PhD at the University of California, San Francisco, was awarded a $1.88 million grant by CureSearch to investigate their hypothesis that drugs that reprogram the epigenome can improve outcomes for children with high-risk medulloblastoma. Researchers believe that cancers become resistant to treatment because they have mutations in a group of proteins that control epigenetics. Epigenetics inform which regions of DNA to read and which to ignore and, thus, which genes are expressed. The inappropriate expression and/or silencing of genes may enable cancer cells to change in response to the therapy and become resistant. To conduct their research, the team will first map the genetic changes (mutations) in genes regulating access to chromatin, which is a complex group of proteins that surround and compact the DNA. Then, based on their findings, they are testing medications on high-risk medulloblastoma specimens obtained from patients and in mouse medulloblastoma models. Dr. Weiss and his team are working to develop new treatments for high-risk medulloblastoma by identifying mutations in epigenetic regulators and using drugs that target these mutations.

As of the conclusion of his CureSearch-funded project, Dr. Weiss has identified promising epigenetic-based therapeutic options for medulloblastoma:

• 28 patient-derived medulloblastoma tumors analyzed to determine genes that change in response to chemotherapy
• 3 epigenetic targets identified
• 61 primary medulloblastoma tumors analyzed by chromatin immunoprecipitation to look for active and repressive histone marks
• 7800 compound high-throughput drug screen performed
• 3 drugs in preclinical testing for treatment of medulloblastoma