Overcoming Resistance in High Risk Medulloblastoma




"'Reprogramming' cancer cells to treat
high-risk brain cancer."

What This Project Does

 
  • William Weiss, MD, PhD
  • Professor of Neurology
    University of California, San Francisco School of Medicine

In the last few years, researchers have learned much more about epigenetics. Epigenetics is the study of how and why certain genes get expressed. This knowledge has allowed scientists to better understand the mutations that cause cancer. The inappropriate expressing and silencing of some genes may cause some types of cancer and make them resistant to treatments that are currently available. A team of international researchers led by William Weiss, MD, PhD at the University of California, San Francisco, has been 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, a type of brain cancer. 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.

When cancers are considered high-risk, it is often because they are resistant to treatment. Medulloblastoma is difficult to cure using conventional treatments like chemotherapy. Researchers believe that these cancers are resistant to treatment because they have mutations in a group of genes that control epigenetics, a group of proteins that tell the cell which regions of DNA to read, and which to ignore. 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 will begin testing medications on high-risk medulloblastoma specimens taken from patients during surgery, and in mice that have been genetically engineered to have this cancer. Their hope is that within three years, they can both identify and develop treatments that can be moved to a Phase I clinical trial in patients.

Potential Impact on Children

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 treatments for refractory cancers (those resistant to treatment) are crucial. Dr. Weiss's work attempts to understand how brain cancer cells are "programmed" by the epigenome, and thus how to "reprogram" them to improve treatments for children with medulloblastoma.

Project Updates

6-Month Research Update - June 2014

As a CureSearch Acceleration Initiative grantee, Dr. Weiss and his team have worked to map different types of mutations that cause medulloblastoma to become resistant to treatment. Dr. Weiss's team has discovered a pattern in mutations in the highest-risk disease. These mutations have much higher levels of methylation, which is a chemical process that regulates how genes are expressed. When methylation works well, the body produces the right number and type of cells. When it malfunctions, as it does during cancer, some cells are overproduced and others are under-produced. Dr. Weiss and his team believe that understanding how methylation becomes abnormal in medulloblastoma will enable them to treat children with this tumor. To approach this problem, Dr. Weiss's team plans to use a combination of chemotherapy and "epigenetic modulators," drugs that target methylation.

The first stage of testing new treatments is creating mouse models that mirror epigenetic abnormalities in human cancer, allowing researchers to test different compounds that will inhibit the growth of certain types of medulloblastoma. The team has recently developed an effective model that they are using to test different compounds, one of which was very effective in inhibiting tumor growth. This effective compound had the additional benefit of being non-toxic to normal cells. This means that it treated the cancerous cells but did not affect normal cells. Dr. Weiss and his team have published four articles on their research this year.

Going forward, Dr. Weiss and his team plan to continue investigating the molecular mechanisms of medulloblastoma cells to understand how these epigenetic regulators work. This will allow them to design a clinical trial for children that uses epigenetic modulators to treat tumors that do not respond to conventional chemotherapy. If these trials are successful, they could lead to a new treatment that is both effective and easier to tolerate than chemotherapy.

Acknowledgments

This program supported in part by generous contributions from the Team Jack Foundation. For more information about the Team Jack Foundation, visit www.teamjackfoundation.org.


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