Uncovering new approaches to target FOXR2 in pediatric cancers
Diffuse midline glioma (DMG) is a deadly pediatric brain cancer. Despite radiation treatment, nearly all children diagnosed with the disease succumb to it with a median survival of 12 months. There have been few advancements in treatment, and current treatment has no curative intent. Therefore, there is a dire need to develop new therapeutic strategies to improve the terrible outcomes for these children and improve quality of life. Looking at genes that are turned on or off in a particular type of cancer can be helpful to figure out what is causing the cancer to grow. One such gene which we found to be turned on in DMG is FOXR2. Interestingly, FOXR2 is normally turned off in normal brain. I have previously studied how FOXR2 is turned on and found new FOXR2 promoters. When a gene is turned on, the promoter is the part of DNA that is turned on first. When the FOXR2 promoter is turned off, DMG cancer cells die and FOXR2 is also turned off. One of the challenges with delivering treatments to brain tumors is overcoming the blood brain barrier, the normal protection that surrounds the brain. Lipid nanoparticles can be used to deliver drugs that can efficiently cross this barrier. This is a promising approach to treating FOXR2-expressing DMGs. In addition to DMGs, I have previously found that FOXR2 is turned on in many pediatric cancers, including neuroblastoma and rhabdomyosarcoma. This is important because the role of FOXR2 is more broad than we previously realized.
Project Goal:
In this project, we will study how to turn off FOXR2 by using small interfering RNAs (siRNA) that block the FOXR2 promoter and are able to turn off FOXR2 in DMG cells. We will place the siRNA that targets the FOXR2 promoter into lipid nanoparticles. We plan to test these nanoparticles in patient-derived DMG cancer cells. Then, we plan to test these nanoparticles in a mouse model of DMG to see if this treatment makes tumors shrink. We will work closely with our collaborator at CHLA who has extensive experience in making and using these nanoparticles, and we will also work together with the Small Animal Imaging Core at CHLA that will be able to accurately assess brain tumor size in mice. Lastly, we will determine whether we can target FOXR2 promoters in other pediatric cancers, specifically neuroblastoma and alveolar rhabdomyosarcoma. Ultimately, our goal is to determine whether we can target FOXR2 in pediatric cancers to improve outcomes for children and their families.
