2. Academic Validation
  3. CD30 and ALK combination therapy has high therapeutic potency in RANBP2-ALK-rearranged epithelioid inflammatory myofibroblastic sarcoma

CD30 and ALK combination therapy has high therapeutic potency in RANBP2-ALK-rearranged epithelioid inflammatory myofibroblastic sarcoma

  • Br J Cancer. 2020 Sep;123(7):1101-1113. doi: 10.1038/s41416-020-0996-2.
Ashleigh M Fordham 1,  Jinhan Xie 1,  Andrew J Gifford 1 2,  Carol Wadham 1,  Lisa T Morgan 1,  Emily V A Mould 1,  Mitali Fadia 3,  Lei Zhai 1,  Hassina Massudi 1,  Zara S Ali 4,  Glenn M Marshall 1 5 6,  Robyn E Lukeis 7,  Jamie I Fletcher 1 6,  Karen L MacKenzie  # 4 8,  Toby N Trahair  # 9 10 11
Affiliations

Affiliations

  • 1 Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia.
  • 2 Department of Anatomical Pathology, Prince of Wales Hospital Randwick, Randwick, NSW, Australia.
  • 3 ACT Pathology, The Canberra Hospital, Garran, ACT, Australia.
  • 4 Children's Medical Research Institute, Westmead, NSW, Australia.
  • 5 Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia.
  • 6 School of Women's and Children's Health, UNSW Sydney, Kensington, NSW, Australia.
  • 7 Cytogenetics Laboratory, SydPath, St Vincent's Hospital, Darlinghurst, NSW, Australia.
  • 8 Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia.
  • 9 Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia. [email protected].
  • 10 Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia. [email protected].
  • 11 School of Women's and Children's Health, UNSW Sydney, Kensington, NSW, Australia. [email protected].
  • # Contributed equally.
PMID: 32684628 DOI: 10.1038/s41416-020-0996-2
Abstract

Background: Epithelioid inflammatory myofibroblastic sarcoma (eIMS) is characterised by perinuclear ALK localisation, CD30 expression and early relapse despite crizotinib treatment. We aimed to identify therapies to prevent and/or treat ALK inhibitor resistance.

Methods: Malignant ascites, from an eIMS patient at diagnosis and following multiple relapses, were used to generate matched diagnosis and relapse xenografts.

Results: Xenografts were validated by confirmation of RANBP2-ALK rearrangement, perinuclear ALK localisation and CD30 expression. Although brentuximab-vedotin (BV) demonstrated single-agent activity, tumours regrew during BV therapy. BV resistance was associated with reduced CD30 expression and induction of ABCB1. BV resistance was reversed in vitro by tariquidar, but combination BV and tariquidar treatment only briefly slowed xenograft growth compared with BV alone. Combining BV with either crizotinib or ceritinib resulted in marked tumour shrinkage in both xenograft models, and resulted in prolonged tumour-free survival in the diagnosis compared with the relapse xenograft.

Conclusions: CD30 is a therapeutic target in eIMS. BV efficacy is limited by the rapid emergence of resistance. Prolonged survival with combination ALK and CD30-targeted-therapy in the diagnosis model provides the rationale to trial this combination in eIMS patients at diagnosis. This combination could also be considered for other CD30-positive, ALK-rearranged malignancies.

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