Investigation of SMARCAL1 as a targetable dependency in BRAF-mutant gliomas
Brain cancers are now responsible for more childhood deaths than any other cancer. The most commonly diagnosed childhood brain cancers are known as gliomas. Pediatric gliomas frequently have mutations in the gene BRAF, which causes BRAF to transmit excessive growth signals, leading to uncontrolled cell division. Currently, some drugs are being used to treat pediatric gliomas which inhibit BRAF and switch off the growth signals. Patients generally respond well to these drugs and their tumors stop growing; however as soon as the therapy is removed, up to 75% of patient tumors return. Using these drugs for long periods can result in excessive toxicity, and so we need alternative methods to treat these tumors that have longer lasting effects. To discover new therapeutic avenues for the treatment of pediatric brain cancers, our group has created cell models of pediatric gliomas that contain the same BRAF mutations found in patient tumors. We then used gene editing methods to systematically inactivate every gene present in these glioma-like cells, with the goal of finding genes that when removed negatively impact the growth of cancer cells, whilst having limited effects on healthy cells. Our analysis of this screen revealed a hit protein called SMARCAL1 that, when inhibited, selectively stopped the growth of BRAF-mutant cancer cells. I believe that SMARCAL1 has a critical role in the growth of glioma cells and so may be a novel therapeutic target.
Project Goal:
The goal of my project is to understand why SMARCAL1 is important for the growth of BRAF-mutant cancer cells and to investigate if inhibition of SMARCAL1 may be used to treat pediatric brain cancers. SMARCAL1 has two main roles in the cell. Firstly, it helps cells to replicate DNA quickly without introducing errors; this is very important for fast growing cancer cells that need to replicate and divide their DNA often. I will use microscopy methods to visualize how DNA replication is different in BRAF-mutant cells compared to healthy cells and if SMARCAL1 is needed for fast DNA replication specifically in cancer cells. Secondly, SMARCAL1 helps to control which genes in a cell are switched on or off, including genes that help sustain cancer growth. I will therefore investigate how gene expression changes in cancer cells when SMARCAL1 is inhibited. Finally, there are currently no drugs available that target SMARCAL1; we thus need to design new drugs that can switch off this protein and hopefully stop cancer cells growing. Towards this aim, I will perform a screen where I mutate different regions of the SMARCAL1 protein to find which mutations most reduce cancer cell growth. This will reveal the "Achilles' heel" of SMARCAL1 which will allow us to rationally design drugs that target the most vulnerable regions. Together, this work will examine the feasibility of targeting SMARCAL1 to stop cancer growth and may give new hope to children suffering with devastating brain tumors.
