Glioblastoma (GBM) is the most common form of cancer that forms in the brain and one of the most difficult cancers to treat. No new drugs have been approved for GBM therapy in more than a decade. To identify new drugs, our colleagues tested thousands of unique chemicals. Of the chemicals that showed promising activity against GBM cells, we discovered that one chemical, 5J12, blocks a protein called lanosterol synthase (LSS) that is involved in making a key component of human cells: cholesterol. Others have shown that reducing cholesterol levels in GBM cells can kill them effectively. However, there are currently no safe and effective ways to reduce cholesterol in GBM tumors. We showed that 5...

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Glioblastoma (GBM) is the most common form of cancer that forms in the brain and one of the most difficult cancers to treat. No new drugs have been approved for GBM therapy in more than a decade. To identify new drugs, our colleagues tested thousands of unique chemicals. Of the chemicals that showed promising activity against GBM cells, we discovered that one chemical, 5J12, blocks a protein called lanosterol synthase (LSS) that is involved in making a key component of human cells: cholesterol. Others have shown that reducing cholesterol levels in GBM cells can kill them effectively. However, there are currently no safe and effective ways to reduce cholesterol in GBM tumors. We showed that 5J12 reduces cholesterol in GBM cells and kills them. We also showed that a chemical related to 5J12 can be safely given to mice and accumulates in their brains. We propose that chemicals related to 5J12 may represent effective new drugs to treat GBM. We propose to optimize drugs related to 5J12 for GBM therapy and test their activity against GBM cells and tumors. We will work as a team to achieve this goal. Our group has unique expertise in chemistry, drug development, and GBM biology. First, we will create new drugs based on 5J12, evaluate them for desirable properties, and test their ability to block LSS and kill GBM cells. Next, we will select one drug related to 5J12 for detailed testing each year. We will rigorously evaluate selected 5J12-related drugs for safety and efficacy in mice. We will test their ability to safely cause human GBMs grown in mice to shrink. Collectively, our team has decades of experience developing new drugs and our work has led to two clinical trials of new brain tumor therapies, one ongoing trial and one that is slated to begin later this year. If successful, our work will provide the data needed to initiate a clinical trial of a 5J12-related drug in GBM, thus providing a desperately needed new treatment option for patients with brain tumors.

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