Project Goal:

Ependymoma is an aggressive pediatric brain tumor without targeted up-front therapies. Thus, identification and validation of molecular targets that can translate into clinical trials is desperately needed to improve patient outcomes. Over 70% of supratentorial ependymoma are driven by an oncogenic fusion between ZFTA and Rela (ZRFUS). ZRFUS can initiate mural ependymoma development by acting as an oncogenic transcription factor and disrupting gene expression programs, suggesting that ZRFUS represents a lead therapeutic target. I aim to identify direct ZRFUS binding proteins, hypothesizing that specific ZRFUS interacting proteins are required for tumor formation and may be targeted therapeutically. I have identified both canonical and non-canonical NFkB proteins consistent with Rela-mediated transcriptional activity using nuclear Rapid Immunoprecipitation and Mass Spectrometry Analysis of Endogenous Proteins of HA-tagged ZRFUS protein. In addition, I have identified a large series of novel chromatin-binding proteins as candidates potentially required for ZRFUS mediated tumorigenesis. I aim to validate key ZRFUS protein interaction dependency and elucidate functionality as well therapeutically target components of the NFkB pathway relevant for ZRFUS mediated transcriptional activation using peptide inhibitors. These aims may elucidate key interactions required for tumor formation in order to identify new therapeutic targets.

Project Update 2024:

Ependymoma is an aggressive pediatric brain tumor with limited treatment options and no straightforward targets for therapies. Thus, identification and validation of molecular targets that can translate into clinical trials is desperately needed to improve patient outcomes. Approximately two thirds of supratentorial ependymoma are driven by the ZFTA-RELA gene fusion; ZFTA is a recently described gene with a role in DNA binding and transcriptional regulation, while RELA (or p65) is a known principal mediator of the canonical NFkB pathway, a pathway known to play a role in many human cancers. The next most common supratentorial subgroup is driven by YAP fusion, a known oncogene that functions in the HIPPO kinase cascade. The ZFTARELA gene fusion (ZRFUS) and YAP fusions can initiate ependymoma development in mice by acting as gene regulators that disrupt gene expression programs, suggesting that these fusions represent a lead therapeutic target for supratentorial ependymoma. My project aims to identify direct ZRFUS binding proteins, hypothesizing that specific ZRFUS interacting proteins are required for tumor formation and may be targeted therapeutically. Interestingly, our findings demonstrate YAP activation across all supratentorial ependymoma subtypes and shows cross-talk of ZFTA-RELA fusion protein and NFkB pathway members with YAP/Tead pathway proteins to regulate gene expression in ZFTA-RELA fusion ependymoma. When YAP is knowcked out, tumor initiation is prevented. This study suggests that intersectional oncogenic transcriptional programs involving ZFTA-RELA and YAP-TEAD networks may contribute to the pathogenesis of supratentorial ependymoma.