Childhood Cancer

You are here

Functional Characterization of RELA Fusion Ependymoma as a Basis for Therapeutic Targeting

St. Jude Children’s Research Hospital
Stephen Mack, PhD
Grant Type: 
'A' Award Grants
Year Awarded: 
Type of Childhood Cancer: 
Project Description: 


Ependymoma is a lethal pediatric brain tumor that is still treated by surgery and radiation. When tumors recur, which is often, patients have limited treatment options and often receive additional radiation further worsening neurologic side effects. Novel, effective and less-toxic therapies are desperately needed for these patients. Ependymomas that arise in the forebrain are frequently driven by an oncogene that joins two proteins, C11ORF95 and RELA (denoted as C11ORF95-RELA fusion). When introduced in murine models, C11ORF95-RELA fusion is sufficient to induce tumors that resemble ependymoma, thus implicating this fusion protein as a key contributor of the disease. However, the mechanism by which C11ORF95-RELA protein functions is unknown. Whether C11ORF95-RELA can be inhibited by drug compounds has not been studied.

Project Goal

Our proposal aims to delineate the function of C11ORF95-RELA using a variety of genetic technologies and bioinformatic approaches. Further, we have developed novel murine models driven by C11ORF95-RELA for studying the biology of this fusion protein. Our ultimate goal is to learn more about the mechanisms of C11ORF95-RELA in cancer and uncover drug compounds that can destroy C11ORF95-RELA tumors in murine models. This model-preclinical data is needed for our efforts to advance effective drugs into clinical trials for patients with C11ORF95-RELA ependymoma.

Project Update (June 2019)

Dr. Stephen Mack is using his ALSF ‘A’ Award to accelerate breakthroughs for ependymoma. Using genomic data made available by the Childhood Cancer Data Lab as well as data through his own studies, Dr. Mack has worked to identify the key biological and molecular characteristics of ependymoma. These characteristics could become the targets for drugs that kill ependymoma cells.

Dr. Mack is currently studying the C11ORF95-RELA oncogenic fusion, which is formed when two separate genes join together. This specific fusion seems to drive the development of certain types of ependymoma. While he learns more about how this fusion works in cancer, Dr. Mack is also working to uncover drug compounds that can destroy ependymoma.

He first began studying genetic targets for ependymoma with an ALSF Young Investigator grant in 2015.

"While treatments have improved for many other childhood malignancies, pediatric brain tumors still remain the leading cause of cancer-related death in children. Investment from ALSF has been instrumental to our biological discoveries in ependymoma, a highly malignant brain tumor for which treatment has not changed for 20 years. Our ALSF supported project on the identification of non-mutated cancer dependency genes has led to new therapeutic leads for treatment of ependymoma. More broadly, our work has provided insight to new targets in other aggressive childhood brain tumors including diffuse intrinsic pontine glioma (DIPG) and glioblastoma. We are grateful for the commitment of ALSF to accelerate the search for brain tumor cures through advancement in scientific and translational discovery” said Dr. Mack.

Project Update (May 2020)

RELA fusion-positive ependymoma carries a poor prognosis, and ependymomas, in general, are resistant to chemotherapy. Despite understanding that RELA gene fusions drive the development of ependymoma, molecular targets remain elusive, and new therapies are critically needed.

Dr. Stephen Mack, PhD is doing just that. His lab studies the C11ORF95-RELA gene fusion that is the most recurrent driver in ependymoma located in the supratentorial region of the brain, with over 70% of this ependymoma subtype carrying a RELA gene fusion. Dr. Mack’s team has discovered genes that RELA fusion-positive ependymomas are dependent upon, which may provide new therapeutic targets. They will work to validate these targets, in addition to learning more about the underlying biology of these tumors, providing insight into future therapeutic strategies.

Learn more about Dr. Mack’s ependymoma research in one of his recent publications in the journal Nature, “Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling”.