Finding new pharmacological approach for neuroblastoma treatment

By Ajay V. Patil

Neuroblastoma – Why we need new treatment?

Neuroblastoma is among the top malignancies in younger patients (less than 15 years). Patients with 18 months of age or older, who present metastatic disease usually come under ‘high risk disease group’. Disease recurs in about 50% of children despite the standard treatment. Hence this section of patients is in dire need of new treatment approaches.

Genomic scenario

In this age of targetable drug discovery and design, it is important to look at the genomic background of any malignancy.

• Recurrent point mutations are rare, but when present they are largely enriched in genes with epigenetic functions like ARID1A, ARID1B, and ATRX. Activity of epigenetic modifiers is also emphasized in previous neuroblastoma studies.
• High-risk neuroblastoma is mostly characterized by segmental chromosomal aberrations.
• Copy-number alterations of MYCN gene is a common feature in nearly one third of patients.

New class of treatment against neuronal malignancies

Recently Lochmann et al., Sci. Transl. Med. 10, (2018) identified epigenetic-targeted inhibitor against neuroblastoma. Following are the key features of this study,

• Revealed hypersensitivity of neuroblastoma cells to GSK-J4, using high-throughput drug screening of epigenetic-targeted therapies and the panel of around 800 cell lines.
• GSK-J4, inhibits two histone (H3K27) demethylases – UTX and JMJD3.
• Using animal model studies, they confirmed the activity of GSK-J4 monotherapy in neuroblastoma.
• Retinoic acid and venetoclax (BCL2 inhibitor) were found to enhance the activity of GSK-J4.

Couple of other studies, have shown the activity of GSK-J4 in other devastating malignancies like, pediatric neural cancer (Grasso et al., Nat Med. 2015) and diffuse intrinsic pontine glioma (DIPG) (Hashizume et al., Nat Med. 2014).

It is vital to find out how this combination of inhibitors will react with conventional chemotherapy and whether H3K27 methylation varies with age considering, the age at diagnosis is a critical prognostic indicator in neuroblastoma. Previous and ongoing clinical studies on epigenetic modifiers vorinostat (NCT00217412 and NCT01208454) and venetoclax (NCT03236857) can also be very useful in designing combination trials. Overall, GSK-J4 emerges as a new candidate for the treatment of this aggressive pediatric malignancy. Successful clinical trials will hint at the new class of drugs for further investigation.

References

1. https://www.nejm.org/doi/full/10.1056/NEJMcibr1806782?query=featured_home#
2. https://www.ncbi.nlm.nih.gov/pubmed/29769286?dopt=Abstract
3. https://www.ncbi.nlm.nih.gov/pubmed/25939062?dopt=Abstract
4. https://www.ncbi.nlm.nih.gov/pubmed/25401693?dopt=Abstract

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