New Treatment Approach in Neuroblastoma Proposed

Pam Harrison

August 01, 2019

A new oncogene that is clearly involved in the pathogenesis of neuroblastoma has been identified by Australian researchers, who say this discovery raises hopes for new therapies.

Indeed, a combination drug strategy that targets the gene and its functions has already been shown to dramatically shrink tumors in mouse models of the disease.

The research was published online July 25 in Nature Communications.

"In this study, we have found that the JMJD6 (jumonji domain-containing 6) gene is gained in approximately 80% of human neuroblastoma tissues," the authors write.

"Treatment with THZ1 and the histone deacetylase (HDAC) inhibitor panobinostat…led to neuroblastoma tumor regression in mice…suggesting this combination as a therapeutic approach for neuroblastoma," they add.

The drugs used in the mouse study are already available, they note. The CDK7 inhibitor THZ1 is currently being explored in cancer clinical trials and the HDAC inhibitor panobinostat (Farydak, Novartis) is already being used in clinical practice in the treatment of multiple myeloma.

Study Details

"The most common gene copy number variation in human neuroblastoma is chromosome 17q21-ter gain, which predicts poor patient prognosis," lead author Matthew Wong, PhD, Children's Cancer Institute, Randwick Sydney, Australia, and colleagues write.

The JMJD6 gene located at chromosome 17qter is one of the few histone modification genes located within the 17q21-ter region.

In datasets of tissues from neuroblastoma patients, analyses indicated that the JMJD6 gene was gained in every human neuroblastoma tissue with 17q gain and that the chromosome 17q/JMJD6 gene was gained in 82.3% of the human neuroblastoma tissues analyzed.

Researchers also assessed the clinical relevance of JMJD6 in human neuroblastoma tissue using comparative genomic hybridization (array-CGH) datasets from 209 patients.

They confirmed that high levels of JMJD6 mRNA expression in these tissues were associated with the most aggressive form of neuroblastoma in about one quarter of patients with the malignancy.

They also showed that high levels of JMJD6 mRNA expression were associated with poor overall and event-free survival rates, and that this was independent of disease stage and age at time of diagnosis, which are twokey prognostic features in neuroblastoma.

Further research indicated that the same gene both induces neuroblastoma cell proliferation and cell survival, and that it is also important for the progression of neuroblastoma in vivo.

New Therapeutic Target

Next, the team examined the synergistic effect of a CDK7 inhibitor, THZ1, and the HDAC inhibitor, panobinostat, to inhibit neuroblastoma cell proliferation and survival.

"THZ1 or panobinostat alone reduce tumor growth in mice," the investigators report.

Importantly, however, the "THZ1 and panobinostat combination therapy synergistically reduced tumor progression and resulted in tumor regression [again] in mice," they add.

The treatment effect of the combination of these two drugs was also quite dramatic, the authors noted in a statement, reducing tumor size by 80% compared with controls after only 3 weeks of treatment.

"Our data…confirm the critical role of JMJD6 in neuroblastoma tumorigenesis," the researchers conclude.

In addition, "our findings identify a CDK7 inhibitor and HDAC inhibitor combination therapy as a treatment strategy for neuroblastoma." 

The study authors have disclosed no relevant financial relationships.

Nature Communications. Published online July 25, 2019. Full text

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