Elucidating the tumor promoting roles of itaconate in ZFTA-RELA Fusion driven ependymomas
Ependymomas are lethal malignancies that bear a dismal prognosis and lack curative treatment strategies despite decades of research. More than 70% of childhood hemispheric ependymomas bear recurrent ZFTA-RELA fusions. Despite these advances, there are no effective treatments, targeted therapies, or clinical trials for ZFTA-RELA ependymomas. Therefore, there is a major knowledge gap and an urgent and unmet need to identify ZFTA-RELA-specific oncogenic mechanisms. Tumor cells alter nutrient uptake and utilization. This is a fundamental hallmark of cancer. Tumor-driving oncogenes, like the ZFTA-RELA fusion, rapidly alter metabolism to promote tumor growth. This proposal aims to target this altered metabolism as a possible treatment strategy. Our proposed research in ZFTA-RELA ependymomas will provide mechanistic advancements by a) defining molecular mechanisms of ZFTA-RELA fusion-driven itaconate metabolism and b) determining the therapeutic potential of inhibiting itaconate production in these tumors.
Project Goals
A majority of hemispheric ependymomas are driven by gene fusions between RELA/p65 part of the fusion activates aberrant NF-kB signaling, while the ZFTA partner causes chromatin remodeling. I show that these tumors rapidly reprogram glucose metabolism to enhance the production of itaconate which is key in driving these tumors. My proposed research will unravel novel ZFTA-RELA-driven mechanisms by which itaconate promotes these aggressive ependymomas and will test if inhibition of itaconate production can be therapeutic. Thus, we expect the outcomes of my proposal to illuminate how ZFTA-RELA fusion-driven ependymomas depend on itaconate and more importantly, aid in the development of new and effective treatment strategies.
