Hyperactivating oncogenic ETS factors to selectively target CIC-rearranged sarcomas
Soft tissue sarcomas (STS) represent a diverse and complex group of cancers that disproportionately affect pediatric and adolescent patients. With more than 80 different subtypes already, the list continues to expand as sequencing-based diagnostic assays become more readily available. CIC::DUX4 sarcoma is a new STS entity characterized by a novel gene fusion between CIC and DUX4. Due to the aggressive nature of the disease and the high rate of chemo-resistance, prognosis is exceptionally poor with less than half of all patients surviving beyond 5 years. Despite the urgent need to find more effective therapies, progress is stalled by the unavailability of primary tissues, small patient numbers, and the scarcity of authentic model systems. In addition to building the foundational resources, tools, and datasets needed to begin tackling this challenging disease, this project will examine the role of downstream ETS factors in oncogenesis and the therapeutic potential of modulating ETS expression/activity to selectively target CIC::DUX4 sarcoma cells.
Project Goals
The usual approach for developing precision cancer therapies is to inhibit the oncogenic drivers or signaling pathways that sustain uncontrolled growth. Mounting data in Ewing sarcoma and other malignancies now indicates that cancer cells may be just as sensitive to pharmacologic and genetic factors that hyperactivate these pathways, opening the door to a new, albeit counterintuitive, class of targeted therapies. The primary goal of this project is to investigate this goldilocks paradigm in CIC::DUX4 sarcoma, a newly recognized and devastating pediatric sarcoma. Our preliminary genome-wide CRISPR/Cas9 screens and multiomics datasets point to oncogenic ETS factors as critical downstream regulators of the CIC::DUX4 sarcoma transcriptional program. Intriguingly, they also uncovered an essential role for the CUL4-E3 ubiquitin ligase complex which constrains ETS transcriptional activity and CIC::DUX4 sarcoma cell differentiation. Here, we will use cutting edge genomic and proteomic technologies to mechanistically dissect the dose-dependent effects of ETS factors in sarcoma and the potential of targeting this axis as a novel treatment strategy.
