Dr. Xiaofeng Wang is a postdoctoral fellow in the Department of Pediatric Oncology at the Dana-Farber Cancer Institute working under the mentorship of Dr. Charles Roberts (Primary mentor), a leading researcher in cancer epigenetics and Dr. Stuart Okin (Co-mentor), a leading expert in stem cell, hematopoietic development and cancer. Building on Dr. Wang's scientific training, he is now proposing to define the Role of SNF5 in regulating SWI/SNF complex assembly & targeting in rhabdoid tumor. Research: Recent cancer genome sequencing studies have identified that several subunits of the SWI/SNF chromatin remodeling/tumor suppressor complex are mutated in 20% of all human cancers. Among these, SNF5 (also known as SMARCB1/INI1/BAF47), a core subunit of the complex, was found to be recurrently mutated in almost all cases of malignant rhabdoid tumors (RT), rare but highly aggressive and lethal cancers that strike young children for which a cure still remains elusive. However, the mechanism by which SNF5 loss affects the SWI/SNF complex function remains unclear. I recently identified ARID1A and ARID1B as key components required for the assembly of the intact SWI/SNF complex and linked complex assembly to cancer cell survival (Nature Medicine, 2014). I have now discovered that SNF5 mutation results in reduced levels of ARID1A, ARID1B and a destabilized residual SWI/SNF complex, indicating SNF5 may play an essential role in regulating the complex activity. The central hypothesis to be explored in this proposal is that aberrant assembly and targeting of residual SWI/SNF complexes leads to activation and/or repression of pathways vital to the development of rhabdoid tumors and the mechanism and consequences of this aberrant activity warrants further intensive investigation. My key objective is to elucidate how SNF5 mutation affects the SWI/SNF complex activity and how this contributes to rhabdoid tumorigenesis and to identify targets for therapeutics.
The specific aims for this proposal are: 1) define the effects of SNF5 mutation upon assembly of the SWI/SNF chromatin remodeling complex and characterize the composition and stability of the residual cancer-driving complex in SNF5-mutant rhabdoid tumors; 2) elucidate how SNF5 mutation affects SWI/SNF complex targeting and transcriptional regulation in rhabdoid tumors; 3) identify specific vulnerabilities conferred by SNF5 mutation in rhabdoid tumors. In this proposal, proteomics, genomics and epigenomics approaches will be performed on rhabdoid tumor cell lines as well as primary cells from transgenic mice to define the role of SNF5 in controlling SWI/SNF complex activity and to establish the fundamental mechanism(s) by which loss of this chromatin regulatory subunit drives rhabdoid tumor development. Candidate Career Goals and Development Plan: My long-term career goal is to become an independently funded cancer biologist with expertise in functional cancer epigenetics and translational research. Specifically, I hope to translate the knowledge gained from my experimental studies into effective therapy for rhabdoid cancer and related SWI/SNF-mutant cancers. The K99/R00 award will help me get advanced training in order to achieve this career goal. This research proposal is part of a structured plan with scientific, technical, and career development components. The research will be performed under the guidance of Drs. Charles Roberts and Stuart Orkin in the Department of Pediatric Oncology at Dana-Farber Cancer Institute. The career development plan builds upon my prior research with the goal of ensuring that I acquire the expertise required to become a successful, independent investigator with a focus on cancer epigenetics. Environment: The Dana-Farber Cancer Institute (DFCI) and Harvard Medical School are internationally recognized research programs with a number of expert researchers in the areas of cancer biology, cancer epigenetics and bioinformatics. Furthermore, the Department of Pediatric Oncology at DFCI and Division of Pediatric Hematology/Oncology at Boston Children's Hospital/DFCI have a distinguished record of training successful scientists and physicians. I have assembled an excellent mentoring and advisory committee, consisting of Dr. Charles Roberts, Dr. Stuart Orkin, Dr. Myles Brown, Dr. Ramesh Shivdasani and Dr. Peter Park, that will guide my research and training experiences, and help me transition to become an independent investigator.
Twenty percent of human cancers have mutations in subunits of the chromatin remodeling SWI/SNF complex. This proposal describes an innovative approach to study the tumor suppressor activity of SNF5, a core member of the complex, which is lost in nearly all cases of malignant rhabdoid tumors, an aggressive and lethal pediatric cancer. The long-term goals of this project are to determine how cancers arise when the complex is mutated and to develop new anticancer therapies that specifically target cells harboring SWI/SNF mutations.