{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 24,
  "authors": [
    {
      "name": "A. Kamili"
    },
    {
      "name": "B. A. Hearn"
    },
    {
      "name": "I. Temelkoska"
    },
    {
      "name": "J. Solomon"
    },
    {
      "name": "M. S. Wheatley"
    },
    {
      "name": "C. H. T. Bui"
    },
    {
      "name": "C. J. Atkinson"
    },
    {
      "name": "L.-J. Elhassadi"
    },
    {
      "name": "S. Qureshi"
    },
    {
      "name": "J. Murray"
    },
    {
      "name": "R. Cadiz"
    },
    {
      "name": "A. J. Gifford"
    },
    {
      "name": "L. Cui"
    },
    {
      "name": "L. Crowley"
    },
    {
      "name": "A. Lin"
    },
    {
      "name": "C. Mayoh"
    },
    {
      "name": "M. Wong-Erasmus"
    },
    {
      "name": "T. W. Failes"
    },
    {
      "name": "G. M. Arndt"
    },
    {
      "name": "M. Haber"
    },
    {
      "name": "M. D. Norris"
    },
    {
      "name": "M. E. M. Dolman"
    },
    {
      "name": "T. N. Trahair"
    },
    {
      "affs": [
        0
      ],
      "name": "J. I. Fletcher"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/76wv1jffsr227.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.06.749004",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.06.749004v1.full",
  "id": "76wv1jffsr227",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.06.749004v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "2728|Neuroblastoma Research and Treatments"
    ]
  ],
  "openalex": "W7212290778",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.06.749004v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-06",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/76wv1jffsr227.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:21:04Z",
      "native_id": "10.64898/2026.09.06.749004",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.06.749004v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Preclinical trial supports dual inhibition of BCL2 and Aurora kinase A for MYCN-amplified high-risk neuroblastoma",
  "title_text": "Preclinical trial supports dual inhibition of BCL2 and Aurora kinase A for MYCN-amplified high-risk neuroblastoma",
  "type": "preprint",
  "updated_at": "2026-10-30T12:21:04Z",
  "url": "https://research.draconitic.com/paper/76wv1jffsr227",
  "venue": "bioRxiv",
  "versions": []
}