Preclinical trial supports dual inhibition of BCL2 and Aurora kinase A for MYCN-amplified high-risk neuroblastoma
Purpose: Treatment for children with high-risk neuroblastoma relies on conventional chemotherapy and anti-GD2 immunotherapy. However, 5-year survival is only 50%, with high rates of late effects. Targeted therapy combinations are a major priority for these patients. The BCL2 inhibitor venetoclax, in combination with cyclophosphamide/topotecan, has clinical activity in relapsed and refractory…
A recent preclinical study indicates that a combination of BCL2 and Aurora kinase A inhibition could represent a more effective treatment option for high-risk neuroblastoma, particularly in cases with MYCN amplification. Conventional treatment for these children currently relies on chemotherapy and anti-GD2 immunotherapy, but 5-year survival rates remain at 50% with significant long-term side effects.
The study's authors sought alternative combinations to improve efficacy and reduce toxicity through systematic preclinical testing.
The researchers used patient-derived xenograft (PDX) models to identify synergistic drug combinations and confirmed these in vivo. They discovered that the combination of venetoclax and alisertib exhibited promising results. This combination proved particularly effective in models of MYCN-amplified neuroblastoma, doubling the median survival time and outperforming the standard chemotherapy combination of cyclophosphamide and topotecan.
The venetoclax-alisertib duo also showed positive results when used alongside anti-GD2 immunotherapy, with animals treated with this combination surviving tumor-free for longer periods.
Interestingly, the study found BCL2 expression and BCL2-Bim complex levels to be of limited value in predicting treatment response. The researchers concluded that their findings support the advancement of BCL2-AURKA inhibition as a potential clinical trial for neuroblastoma, both alone and in combination with anti-GD2 immunotherapy, especially for patients with MYCN-amplified disease.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
