Preclinical trial supports dual inhibition of BCL2 and Aurora kinase A for MYCN-amplified high-risk neuroblastoma
- 1Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre
Abstract
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.
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BibTeX
@misc{kamili2026preclinical,
title = {{Preclinical trial supports dual inhibition of BCL2 and Aurora kinase A for MYCN-amplified high-risk neuroblastoma}},
author = {A. Kamili and B. A. Hearn and I. Temelkoska and J. Solomon and M. S. Wheatley and C. H. T. Bui and C. J. Atkinson and L.-J. Elhassadi and S. Qureshi and J. Murray and R. Cadiz and A. J. Gifford and L. Cui and L. Crowley and A. Lin and C. Mayoh and M. Wong-Erasmus and T. W. Failes and G. M. Arndt and M. Haber and M. D. Norris and M. E. M. Dolman and T. N. Trahair and J. I. Fletcher},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.06.749004},
url = {https://www.biorxiv.org/content/10.64898/2026.09.06.749004v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Preclinical trial supports dual inhibition of BCL2 and Aurora kinase A for MYCN-amplified high-risk neuroblastoma
AU - A. Kamili
AU - B. A. Hearn
AU - I. Temelkoska
AU - J. Solomon
AU - M. S. Wheatley
AU - C. H. T. Bui
AU - C. J. Atkinson
AU - L.-J. Elhassadi
AU - S. Qureshi
AU - J. Murray
AU - R. Cadiz
AU - A. J. Gifford
AU - L. Cui
AU - L. Crowley
AU - A. Lin
AU - C. Mayoh
AU - M. Wong-Erasmus
AU - T. W. Failes
AU - G. M. Arndt
AU - M. Haber
AU - M. D. Norris
AU - M. E. M. Dolman
AU - T. N. Trahair
AU - J. I. Fletcher
PY - 2026
DA - 2026/09/06
PB - bioRxiv
DO - 10.64898/2026.09.06.749004
UR - https://www.biorxiv.org/content/10.64898/2026.09.06.749004v1
AB - 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.
ER -