Editors' ChoiceCancer

A new hope for neuroblastoma treatment?

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Science Translational Medicine  18 Dec 2019:
Vol. 11, Issue 523, eaaz9769
DOI: 10.1126/scitranslmed.aaz9769

Abstract

Combined ALK and PIM1 inhibition may treat high-risk neuroblastomas.

Neuroblastoma is the most common extracranial pediatric solid tumor and can originate through different gene mutations or amplifications. While most neuroblastoma patients are cured, half of patients with high-risk disease will relapse, pointing to a clear need for new treatments.

Trigg and colleagues describe a potential therapeutic combination for anaplastic lymphoma kinase (ALK) positive neuroblastomas, which often become resistant to targeted agents. First, the authors used a CRISPR-based activation screening with a pooled gRNA library to increase the transcription of thousands of genes on neuroblastoma cell lines exposed to ALK inhibitors such as brigatinib or ceritinib. Using this technology, they identified PIM1 gene overexpression as one of the main resistance mechanisms to these inhibitors and decided to further explore PIM1 as a therapeutic target after observing that its augmented expression led to evasion of apoptosis. While reduction of PIM1 mRNA or treatment with AZD1208, a PIM1 inhibitor, was not sufficient to kill ALK-expressing neuroblastoma cells, their combination with ALK inhibitors showed mild synergism. To further investigate the combined inhibition of ALK and PIM1 in vivo, the authors used two ALK-mutant neuroblastoma patient-derived xenograft mouse models. In both cases, ceritinib (currently in clinical trials) or AZD1208 individually only delayed tumor growth, but their combination decreased tumor volume, increased event-free survival, and were well-tolerated in mice. Moreover, gene expression analyses after in vivo treatment with ceritinib found PIM1 mRNA up-regulation, demonstrating its resistance function and correlating with the in vitro findings.

In summary, this elegant study by Trigg and colleagues illustrates how ALK-positive neuroblastoma cells avoid apoptosis when exposed to targeted agents through PIM1 up-regulation. Further, the study uncovers a potential therapeutic combination strategy that, while still requiring further study, holds promise to better treat high-risk neuroblastoma patients.

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