Role of FACT in ZFTA-RelA fusion driven ependymoma

点击翻译按钮获取中文摘要

PROJECT SUMMARY / ABSTRACT Ependymomas are tumors that occur in the brain or spinal cord and are incurable in nearly half of all patients. Recent molecular classification has identified numerous molecular subgroups of ependymoma with supratentorial ependymoma ZFTA-RELA fusion positive (ZFTA-RELA) accounting for over 70% of all supratentorial ependymomas. ZFTA-RELA, a mainly pediatric brain tumor, has also been identified as one of the subgroups with the worst prognosis. These tumors arise from the oncogenic fusion between a central gene in the NF-κB pathway, RELA, and a gene with undescribed function, ZFTA. The resulting fusion protein, ZRfus, aberrantly recruits transcriptional and chromatin remodeling machinery to drive neoplastic transcriptional programs that includes constitutive activation of NF-κB signaling, activation of inflammatory gene expression programs, and stem cell programs. To date, chemotherapy has not become standard of care for any of the subtypes of ependymoma. All targeted therapies tested in ependymoma clinical trials have failed. Therefore, there is an urgent need to capitalize on the more recent molecular understanding of ZFTA-RELA to develop novel therapeutic paradigms that increase survival outcomes for these patients. In the search for co-regulatory proteins as candidate tumor dependencies and targets, we identified the chromatin remodeling complex, FACT (FAcilitates Chromatin Transcription), as a ZRfus interacting protein. Moreover, FACT is elevated in ZFTA-RELA compared to normal brain tissue and other ependymoma disease subtypes. Project goal: To thoroughly investigate FACT as a driver of ZFTA-RELA and to reveal it as a promising therapeutic target for this devastating disease. FACT, a heterodimer of SPT16 and SSRP1, mainly serves to reorganize nucleosomes to facilitate RNA polymerase II-mediated transcription. In tumors, we and others have shown that FACT is essential for maintaining an undifferentiated stem-like state necessary for tumor growth. This is relevant for ZFTA-RELA tumors as they are characterized as having undifferentiated transcriptional profiles. Project hypothesis: FACT regulates ZRfus oncogenic and inflammatory genes to maintain an undifferentiated cell state. Compromising FACT function will lead to reduced tumor growth, modulate tumor inflammation, and improve survival in orthotopic murine tumor models. Aim 1: Determine if FACT is essential for sustaining transcription of ZRfus targets (including oncogenes and inflammatory genes) and stem cell identity genes that may be important for tumorigenicity. Impact: These studies will reveal how FACT regulates ZRfus transcription and tumor cell identity. Aim 2: Evaluate the impact of genetic and pharmacological disruption of FACT on tumor progression, immune landscape, overall survival, and normal neurogenesis. Impact: These studies will reveal preclinical insight into FACT as a therapeutic target, and the efficacy of our candidate small molecule anti-neoplastic as rationale therapy to inform future clinical trial design. Overall, successful completion of our studies will reveal new therapeutic options for ZFTA-RELA ependymoma that can rapidly be moved into clinical trials.