Identifying genomic and compound dependencies in undifferentiated sarcomas
Mentor: William Hahn, M.D., Ph.D. (Harvard Medical School)
The intersection between nanomedicine and precision medicine depends on the understanding of cell pathway mechanisms. For patients with undifferentiated sarcomas, mechanisms are lacking. Undifferentiated sarcomas account for up to 20% of all soft tissue sarcomas and therapies for this type of cancer are ill defined with poor outcomes for those with metastatic disease. We have developed a novel undifferentiated sarcoma cell line from a patient with metastatic disease. This cell line is genomically silent but carries a number of potential novel fusions. Compound screens and a novel shRNA with paired seed control screen have been performed against over 400 drug targets showing dependencies to CDK1, CDK4, TOP2A and XPO1. Genomic editing using CRISPRs to knockout these targets is pending. We aim to validate these dependencies and subsequently determine if one of the novel fusions drives such dependencies. Further, we will look at historical samples to determine if these fusions are prevalent in this subtype of sarcomas. By doing so, we may be able to develop a biomarker for a subset of undifferentiated sarcomas with associated genomic and compound dependencies.
A. Compound sensitivities based on area under the curve for an undifferentiated sarcoma cell line at early versus late passage. Compounds with AUCs of less than 3.5 are considered to be significantly sensitive. The genes related to the 4 compounds highlighted in red also were hits in the shRNA screen. B. Drug sensitivities of the 4 highlighted compounds in an early passage of the undifferentiated sarcoma cell line compared to lung adenocarcinoma cell line control. Source: Dana-Farber Cancer Institute; Broad Institute Source: