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Overcoming Resistance in High Risk Medulloblastoma


“‘Reprogramming’ cancer cells to treat high-risk brain cancer.”

What This Project Does

William Weiss
  • 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

30 Month Research Update

Dr. Weiss, at the University of California, San Francisco, studies high-risk brain tumors in children. High-risk tumors are more aggressive and more likely to relapse. His research is focused on trying to understand how to overcome relapse that is often seen in brain cancer patients following initial treatment. The relapse is caused by the tumor becoming resistant to chemotherapy. Dr. Weiss has identified several therapeutic targets whose activity increases in tumors after chemotherapy. The team focuses on medulloblastoma, an especially aggressive type of brain tumor, that shows frequent relapse and has no known cure. The goal of Dr. Weiss’ research is to test FDA approved drugs or drugs that are currently being tested in adult clinical trials to more rapidly repurpose existing drugs for use in pediatric brain cancer. The hope is to find a therapy that is less toxic that can overcome chemotherapy resistance.

Using genomic analysis, Dr Weiss’ research team has analyzed over 28 brain tumors from medulloblastoma patients to find a set of genes that change in patients post-chemotherapy. Their research points to “epigenetic” changes as the cause for chemotherapy resistance. Epigenetics is the study of how the environment or other factors, like cancer drugs, affects DNA. The Weiss lab has been actively studying three epigenetic targets: LSD1, HDAC1 and MYC. So far, the team has identified commercially developed drugs for each target and has tested these drugs in preclinical studies using advanced animal models of medulloblastoma. By testing pre-approved drugs, Dr Weiss hopes to get these potential cures to children sooner. At the present time, they are focused on a drug targeting HDAC1, and testing its ability to cross the “blood-brain barrier”. Initially, the team had a promising therapy but it was poor in penetrating the brain, therefore it was not a suitable treatment for medulloblastoma. The new compound has a much higher brain penetrance and looks to be very encouraging. Preclinical tests are ongoing to verify the drug is effective for medulloblastoma. Once the preclinical test is complete, the team hopes to move quickly to determine if these compounds will be effective in treating medulloblastoma in pediatric patients.

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.

Overcoming Resistance in High Risk Medulloblastoma was last modified: October 3rd, 2016 by Geoff Duncan

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