Preclinical trial supports dual inhibition of BCL2 and Aurora kinase A for MYCN -amplified high-risk neuroblastoma
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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 neuroblastoma. We sought more effective and safer venetoclax combinations through systematic preclinical testing.
Experimental design
Synergistic combinations were identified by high-throughput screening using patient-derived xenograft (PDX) models and confirmed in vivo . The leading combination (venetoclax-alisertib) was compared to combination chemotherapy in a clinical trial-like study using 22 PDX models, in scheduling experiments designed to reduce short-term toxicity, and in combination with anti-GD2 immunotherapy. BCL2 and Bim-BCL2 complex protein levels were assessed as predictors of sensitivity.
Results
In vitro synergy with venetoclax was observed for standard-of-care chemotherapies and targeted agents, including DNA topoisomerase, microtubule, HDAC and Aurora kinase A (AURKA) inhibitors. Venetoclax-alisertib was particularly effective in vivo . In an n=1 study, venetoclax-alisertib induced objective response in all models. Activity was most striking in models of MYCN -amplified disease (n=12), doubling median survival time compared to cyclophosphamide/topotecan, and outperforming venetoclax-cyclophosphamide-topotecan. Efficacy was maintained with discontinuous schedules, minimizing hematological toxicity without substantially compromising activity. PDX-engrafted animals treated with venetoclax-alisertib and anti-GD2 immunotherapy survived tumor-free long-term. BCL2 expression and BCL2-Bim complex levels were of limited value for predicting response.
Conclusion
Our findings support advancement of BCL2-AURKA inhibition to clinical trial for neuroblastoma with or without anti-GD2 immunotherapy, particularly in patients with MYCN amplified disease.
TRANSLATIONAL RELEVANCE
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, is limited by treatment-related toxicity. Combination drug screening in patient-derived models identified approved drugs synergistic with venetoclax, including the Aurora kinase A 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 and was particularly effective against MYCN -amplified disease (n=12), doubling median survival time compared to cyclophosphamide/topotecan, and outperforming venetoclax/cyclophosphamide/topotecan. Efficacy 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 dual BCL2-Aurora kinase A inhibition to clinical trial for neuroblastoma with or without anti-GD2 immunotherapy.
