Biology and molecular vulnerabilities in SMARCB1-deficient tumors

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

During FY25, we took advantage of sequencing data from a large cohort of patients with chordoma to study SMARCB1-deficient chordoma. We are interested in understanding the biological differences between chordoma from different locations along the spine (clivus vs. sacrum), developing in children vs. adults, and presenting with different histology (conventional vs. poorly differentiated). SMARCB1-deficient chordoma tend to develop in the clivus, in children, and be poorly differentiated. They are a more aggressive form of chordoma with worse prognosis. Because they can develop in early childhood, we hypothesize that inherited variants in the genome may play a role in chordoma formation, possibly by affecting the normal development of the notochord. We are identifying candidate variants in the germline of patients with chordoma and will be looking at the potential role of the altered gene(s) on tumorigenesis and notochord development using the chordoma human cell models we are developing. We are using RNA sequencing of tumors and blood from patients with chordoma to examine expression of potential drug targets and biomarkers compared to normal tissue and blood. Solute transporters play an important role in cell metabolism, transporting building blocks for cellular processes in and out of the cell. We hypothesize that some tumors may develop "addiction" to specific transporters and could be treated by modulating the function of the transporter. Alternatively, these transporters may be useful as biomarkers to diagnose and follow tumor growth and progression. Published data from other groups has demonstrated the importance of certain solute transporters in chordoma proliferation and response to drugs. We are assessing the expression of solute transporters and other metabolic markers in chordoma tumors and patient blood to study whether cellular metabolism is a specific target for chordoma therapy. We will extend these analyses to determine how specific the expression is to chordoma tumors. In the upcoming year, we plan to identify specific solute transporters to study chordoma cell metabolism. We have continued our development of stable chordoma cell lines for use in drug screening studies. We have confirmed findings by others that chordoma cells grow better on specific extracellular matrix. We have successfully marked three poorly differentiated and three conventional human chordoma cell lines, obtained from the Chordoma Foundation biobank, with a red fluorescent marker to follow cell proliferation in high-throughput assays. In the upcoming year we will study loss of SMARCB1 expression in conventional chordoma lines to better understand the role of SMARCB1 loss in the more aggressive poorly differentiated chordomas.