Childhood Cancer

You are here

Function and Dependency of NFkB Activity in ZFTA-RELA Fusion Ependymoma

Institution: 
Baylor College of Medicine
Researcher(s): 
Austin Stuckert, MD
Grant Type: 
Young Investigator Grants
Year Awarded: 
2021
Type of Childhood Cancer: 
Ependymoma
Project Description: 

Brain tumors are the leading cause of cancer related death in children. Ependymoma is an aggressive pediatric brain tumor resistant to chemotherapy, with treatment limited to surgical resection and radiation. Compared to other pediatric cancers, there are drastically fewer targeted agents currently under evaluation in ependymoma clinical trials and no current up-front targeted therapies. One sub-type of ependymoma is driven by the fusion of two genes, one of which is involved in regulation of a molecular pathway (NFkB) common to many cancers. My research aims to better understand the role of the NFkB pathway in driving this sub-type of ependymoma and the key protein interactions required for tumor formation in order to identify new potential drug targets that could be rapidly brought to clinical trials and ultimately improve outcomes in children with ependymoma.

 
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.