Researchers have identified the JMJD6 gene as a critical factor for neuroblastoma tumorigenesis, indicating potential for a new targeted drug therapy treatment strategy.
The most prevalent solid tumor in early childhood cancers, neuroblastoma comprises 15% of total childhood cancer deaths. Neuroblastoma is distinctive from adult cancers in that it is characterized by frequent chromosome copy number variations, and its most prominent features are gene deletion, amplification, or gain. While chromosome 17q21-ter is frequently gained in the most aggressive form of neuroblastoma, it was until now unclear which genes play a critical role in tumorigenesis.
In their study published in Nature Communications, researchers led by Matthew Wong, MD, of the Children's Cancer Institute in Sydney, Australia, evaluated a tumor database of 209 patients and found a candidate gene, JMJD6, that is active in more than 25% of patients with a poor prognosis of neuroblastoma. Identifying JMJD6 as a tumorigenic factor, the researchers found that high levels of JMJD6 expression in tissues are linked to poor prognosis, regardless of disease stage and the patient's age at the time of diagnosis. Turning off the gene in cell lines and in mice led to reduced growth of neuroblastoma cells, reduced tumor progression, and increased survival.
Additionally, Dr. Wong and colleagues determined that a combination therapy of the CDK7/super-enhancer inhibitor THZ1 and the histone deacetylase (HDAC) inhibitor drug panobinostat synergistically reduces JMJD6 expression, thereby blocking disease progression and inducing tumor regression. Using this combination treatment strategy in mice resulted in an 80% reduction in tumor size after three weeks.
"Our data demonstrate that JMJD6 overexpression in neuroblastoma tissues predicts poor patient prognosis, independently of other prognostic markers such as MYCN amplification status, age at the time of diagnosis, and disease stage," conclude Dr. Wong and colleagues. "Our findings identify CDK7 inhibitor and HDAC inhibitor combination therapy as a treatment strategy for neuroblastoma."
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Image credit: Dr. Maria Tsokos