DMG: From SWI/SNF’s role in cholesterol biosynthesis to new therapeutic opportunities
Brain tumors are the second most common childhood cancer and the primary cause of cancer-related death. Diffuse Midline Gliomas (DMG) account for 10% of them and have less than 1% survival at five years. Because of the nature and location of the tumor, surgical removal is not an option, and the standard therapy is radiation, with a short-lived response.
Because standard therapies are not effective, a lot of research is performed with the goal of uncovering potential targeted therapies. Because the driver mutations cannot be directly targeted therapeutically, efforts have been devoted to the understanding of the consequences of these mutations and to the identification of dependencies.
Recent studies have found that a complex called SWI/SNF is important for the growth of DMG. SWI/SNF is like a machine in our cells that rearrange how DNA is packaged, which affects how genes are turned on or off. We have further discovered that DMG cells and tumors make more enzymes involved in making cholesterol compared to normal brain cells. We demonstrate that blocking one of these enzymes in the cholesterol-making process is really effective against DMG cells without hurting normal brain cells. Additionally, the inhibition of SWI/SNF makes DMG cells less sensitive to this cholesterol-making process blocker, suggesting that SWI/SNF plays a role in controlling cholesterol production in DMG tumors.
Project Goal:
Our main goal is to understand how the oncogenic drivers affect DMG so we can find better ways to treat this disease. In this project, we aim to figure out how SWI/SNF influences the production of cholesterol in DMG tumors, which could lead to new treatment options.
To do this, we have two specific goals:
1. Understand how SWI/SNF controls the cholesterol-making process in DMG. We've seen that DMG tumors and cells make more cholesterol compared to normal cells, but we're not sure why. Our preliminary data suggest that SWI/SNF might be involved. By studying DMG cells with and without the oncogenic drivers, as well as normal cells, we will test how SWI/SNF affects the genes involved in making cholesterol.
2. Find new weaknesses in DMG tumors that we can target with drugs. We have found that DMG cells are sensitive to blocking certain enzymes involved in making cholesterol. Also, we know that DMG tumors depend on SWI/SNF to grow. We will test different drugs and combinations targeting both cholesterol and SWI/SNF on DMG cells to see which ones work best without harming normal brain cells. Then, we will try these treatments on mice with DMG tumors to see if they are effective.
By doing this research, we hope to learn more about how SWI/SNF affects DMG and find new ways to treat this incurable disease.
