Intervening in the TP53 Pathway Phosphatome in Pediatric High-Grade Gliomas
Abstract
This proposal addresses Fiscal Year 2020 (FY20) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas: Brain Tumors, Pediatric Brain Tumors and FY20 PRCRP Military Health Focus Area: Mission Readiness. The TP53 pathway is made up of many proteins and has the job of protecting cells in our body from errors or mutations that can cause them to grow too quickly. However, many cancers find ways of turning off the TP53 pathway, which allows them to divide and form tumors. In particular, we (and others) have found pediatric high-grade gliomas, a particularly devastating childhood brain tumor for which no curative treatments exist, to very commonly have mutations in genes that switch off the protective mechanisms of the TP53 pathway. Treatment strategies that are directed toward cancer cells in which TP53 signaling has been switched off stand to benefit children with pediatric high-grade gliomas, in addition to thousands of other cancer patients, since TP53 inactivation is so common across cancers in general. There are many ways in which cells can turn the function of a protein on or off. One very common way in which cells do this is to add a chemical group, such a phosphorus group, to proteins that they wish to turn on or off, much like a Post-it note. Cancer cells have unique signatures of these chemical groups compared to normal cells. Therefore, therapies directed toward specific phosphorus groups that cancer cells need to survive represent a potential way to kill cancer cells while sparing normal cells, thereby reducing side effects. Here, we will apply cutting edge technology to alter the coding sequence of all phosphorylation sites in pediatric high-grade glioma cells that have mutations that turn off the TP53 pathway. By doing this, we hope to identify the specific phosphorylation sites that these cells require to survive. We will then determine whether these sites present potential targets for new treatments. The results generated in this proposal stand to identify a completely novel therapeutic approach for children with pediatric high-grade gliomas. The research strategies described in this proposal can also be extended to other cancers beyond pediatric high-grade gliomas. This proposal addresses FY20 PRCRP Military Health Focus Area: Mission Readiness. Pediatric high-grade gliomas affect families indiscriminately, including military Service Members, Veterans, and military beneficiaries. The diagnosis of a cancer in a child is devastating and negatively impacts mission readiness. Moreover, the approaches outlined in this application can be applied to other cancer types, including those that affect military Service Members, Veterans, and military beneficiaries themselves.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110910
Entities
People
- Rameen Beroukhim
Organizations
- Dana–Farber Cancer Institute
- United States Army