ZFTA-RELA ependymoma: presenting a new therapeutic opportunity through inhibition of nuclear export
Ependymoma, lack of therapies and the secret of the ZFTA-RELA fusion
The ZFTA-RELA fusion is the most common alteration in supratentorial ependymoma (EPN), and it was thought that persistent nuclear localization of this protein drives tumor growth. However, existing drugs cannot directly inhibit this fusion.
Drug targets identified by CRISPR-Cas9 screening
Through a CRISPR-Cas9 pooled screen we identified several druggable candidates including XPO1, CARM1, SMARCA4, and CDK1, with particular focus on the nuclear export protein XPO1. Selinexor, already FDA‑approved, can cross the blood‑brain barrier, facilitating clinical application.
Tumor growth suppression by blocking nuclear export
Inhibition of nuclear export leads to excessive accumulation of ZFTA‑RELA in the nucleus, arresting the cell cycle and preventing tumor cell proliferation. Selinexor monotherapy and its combination with Gemcitabine and Ribociclib markedly extended survival in mouse models.
Future significance and outlook
These findings provide direct guidance for designing new clinical trials for patients with ZFTA‑RELA ependymoma and open a path toward personalized drug combinations that could improve therapeutic success rates in children.
BACKGROUND: Ependymoma (EPN) is the third most common pediatric brain tumor with no targeted therapies available to patients. In supratentorial ependymoma, the most frequent driver alteration is a gene fusion between ZFTA and RELA (denoted ZR), leads to constitutive localization of ZR in the nucleus. Because ZR is not currently druggable, we tested whether ZR expression leads to aberrant protein interactions that could represent therapeutic vulnerabilities. METHODS: Using CRISPR-Cas9 pooled screening, we identified many novel druggable ZR interacting proteins including XPO1, CARM1, SMARCA4, and CDK1. We focused on the nuclear export protein (XPO1), given the ability of most XPO1 inhibitors (i.e. Selinexor) to cross the blood brain barrier, FDA approval, and documented safety profiles in children. RESULTS: We found that specific nuclear ZR levels are needed for cell proliferation and are regulated by XPO1. Increased ZR accumulation in the nucleus does not increase oncogenic gene expression but drives tumor cells out of cell cycle, as compared to a defective ZR DNA binding mutant. Treatment of ZR driven patient-derived mouse models with Selinexor impairs cell growth and extends survival of animals in vivo. The combination of Selinexor treatment with Gemcitabine and Ribociclib (used in a clinical trial for relapsed EPN at St Jude Children's Research Hospital (SJDAWN)) further extends mouse survival. CONCLUSION: Our findings demonstrate that ZR interacting proteins constitute therapeutic leads, and that XPO1 is critical for titrating 'goldilocks' levels of ZR nuclear expression. We identify a novel combination therapy of Selinexor, Gemcitabine, and Ribociclib that may be immediately translated into clinical trials for EPN patients that are currently without targeted treatments. XPO1 inhibition is an effective therapeutic strategy against ZFTA-RELA ependymoma.
This study identified a novel therapeutic strategy targeting the ZFTA‑RELA fusion, which previously lacked a targeted treatment in the most common pediatric ependymoma (EPN). The combination of Selinexor with existing chemotherapeutics could increase treatment success rates and substantially improve the quality of life for affected children when applied to patients.