Neuroblastoma, a prevalent pediatric cancer originating in developing nerve cells outside the brain, poses significant challenges in treatment, with over 40% of patients succumbing to the disease despite advances in therapy. However, a groundbreaking study from the University of Chicago unveils a potential breakthrough in neuroblastoma treatment by targeting RNA modifications associated with the disease.
Published in Cell Reports, the research demonstrates the efficacy of a novel drug molecule designed to inhibit proteins responsible for adding modifications to RNA transcripts, leading to a reduction in neuroblastoma cell growth. Furthermore, the treatment shows promise in suppressing neuroblastoma tumor growth in mouse models, indicating its potential as an effective therapeutic strategy.
Pomaville et. al, underscores the urgency for alternative treatments, citing the current challenges in curing high-risk neuroblastoma and the associated treatment-related toxicities. The study introduces a paradigm shift in therapeutic strategy by employing drugs that alter gene expression through inhibiting RNA-modifying proteins, potentially revolutionizing neuroblastoma treatment. Advancements in genetic sequencing and chemical biology have elucidated numerous genetic links to cancer, revealing the critical role of RNA modifications in gene expression regulation. The researchers investigate the effects of RNA methylation on neuroblastoma.
The study identifies the METTL3/METTL14 complex, responsible for adding the N6-methyladenosine (m6A) modification to RNA transcripts, as a potential therapeutic target in neuroblastoma. High expression levels of METTL3 correlate with lower survival rates in patients, indicating its role in driving tumor growth. Through genetic manipulation and inhibitor testing, the researchers demonstrate the efficacy of METTL3 inhibition in reducing neuroblastoma cell growth and promoting neuronal differentiation. Especially, the inhibitor also exhibits promising results in mouse models, highlighting its potential for clinical application.
Furthermore, the study explores the synergy between METTL3 inhibition and immunotherapy, aiming to transform “cold” neuroblastoma tumors into “hot” tumors susceptible to immunotherapy. Preliminary findings suggest that METTL3 inhibition may enhance the anti-tumor effects of immunotherapy, offering a new avenue for neuroblastoma treatment.
In conclusion, targeting RNA modifications presents a promising therapeutic approach for neuroblastoma, offering hope for improved outcomes and reduced treatment-related toxicities. Further research into the combination of METTL3 inhibitors and immunotherapy holds the potential to revolutionize neuroblastoma treatment, paving the way for enhanced patient care and survival rates.
Reference
Pomaville M, Chennakesavalu M, Wang P, Jiang Z, Sun HL, Ren P, et al. Small-molecule inhibition of the METTL3/METTL14 complex suppresses neuroblastoma tumor growth and promotes differentiation. Cell Reports. 2024 May;43(5):114165.