Preclinical trial supports dual inhibition of BCL2 and aurora kinase for MYCN-amplified high-risk neuroblastoma

Half of all children with high-risk neuroblastoma experience relapse or have refractory disease. These children lack effective options, and few survive beyond 5 years. The BCL2 inhibitor venetoclax, combined with cyclophosphamide/topotecan, has clinical activity in relapsed and refractory neuroblastoma, however with severe treatment-emergent adverse events. Combination drug screening in patient-derived models identified approved drugs synergistic with venetoclax, including the aurora kinase inhibitor alisertib. We assessed venetoclax-alisertib in 22 diverse neuroblastoma PDX models using an n=1 clinical trial-like design. Venetoclax-alisertib induced objective response in all models but was particularly effective in models of MYCN-amplified disease (n=12), doubling median survival time compared to cyclophosphamide/topotecan, and outperforming venetoclax/cyclophosphamide/topotecan. The efficacy of venetoclax-alisertib was maintained with discontinuous schedules, minimizing hematological toxicity without substantially compromising activity. Venetoclax-alisertib was strikingly effective with anti-GD2 immunotherapy, allowing long-term survival of PDX-engrafted animals. Our findings support advancement of venetoclax-alisertib to clinical trial for neuroblastoma with or without anti-GD2 immunotherapy.

• Type: Other
• Archive: European Genome-phenome Archive (EGA)