Charles W. M. Roberts Lab

The Roberts Lab is a committed team of professionally trained scientists and technical staff focused on translational discovery.

History has taught us that the genes mutated in the earliest childhood cancers often have broad cancer relevance. Pediatric malignant rhabdoid tumors, some of the earliest and most aggressive tumors in children, harbor mutations in the SWI/SNF chromatin remodeling complex. Established as the first link between chromatin remodeling and cancer, mutations in genes encoding the SWI/SNF complex subunits are present in more than 20% of all cancers. Inactivating SMARCB1, the SWI/SNF subunit mutant in rhabdoid tumors, results in the extremely fast onset of cancer in 100% of mice.   

Our mechanistic studies are focused on deciphering the normal function of the SWI/SNF complex. We have discovered that this chromatin remodeling complex regulates enhancer elements: regions of the genome that provide instructions for gene expression. It exerts a nucleosome-based control of transcriptional programs that dictate lineage specification in cells.  

In parallel, we are actively investigating mechanisms by which perturbation of the SWI/SNF complex leads to cancer formation. We utilize mouse models combined with molecular, cellular, and biochemical approaches to characterize mechanisms of tumor suppression and to identify novel therapeutic targets. Our research on the relationship between the SWI/SNF complex and polycomb silencing complexes formed the basis for the 2020 FDA approval of the EZH2 inhibitor tazemetostat for SMARCB1-deficient cancers. 

Traditional approaches to understanding genetic vulnerabilities in cancer are limited by a paucity of mutational clues, particularly in pediatric cases, and a pace inconsistent with the need for discovery. As such, we collaborated with colleagues at Dana Farber and the Broad Institute to initiate the Pediatric Cancer Dependencies Project. The work continues here at St. Jude and has expanded to include genome wide screens of more than 200 cancer cell lines. This project yields targets with potential for clinical actionability, and robust data that has led to a first of its kind pediatric specific clinical trial with pharmaceutical partners.  

Looking forward, we seek to understand how sub-families of SWI/SNF complexes cooperatively function to generated integrated control of transcription, and to identify and translate novel therapies.