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Published on: November 12, 2019
CD30 and ALK combination therapy has high therapeutic potency in RANBP2-ALK-rearranged epithelioid inflammatory
Ashleigh M Fordham1, Jinhan Xie1, Andrew J Gifford1,2
1Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia.
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.
Insights
Epithelioid inflammatory myofibroblastic sarcoma (eIMS) shows resistance to ALK inhibitors. Combining CD30-targeted therapy with ALK inhibitors may offer improved outcomes for eIMS patients.
Area of Science:
- Oncology
- Cancer Research
- Pharmacology
Background:
- Epithelioid inflammatory myofibroblastic sarcoma (eIMS) is characterized by ALK rearrangement, CD30 expression, and frequent relapse.
- Resistance to ALK inhibitors like crizotinib is a significant clinical challenge in eIMS.
Purpose of the Study:
- To identify effective therapies for ALK inhibitor resistance in eIMS.
- To evaluate combination therapies targeting both ALK and CD30.
Main Methods:
- Matched diagnosis and relapse xenografts were generated from malignant ascites of an eIMS patient.
- Xenografts were characterized for RANBP2-ALK rearrangement, ALK localization, and CD30 expression.
- In vivo efficacy of single-agent and combination therapies (brentuximab vedotin, tariquidar, crizotinib, ceritinib) was assessed.
Main Results:
- Brentuximab vedotin (BV) showed single-agent activity but tumors regrew, associated with reduced CD30 and increased ABCB1.
- BV resistance was partially reversed by tariquidar in vitro, but combination therapy showed limited efficacy in vivo.
- Combination therapy with BV and either crizotinib or ceritinib induced significant tumor shrinkage and prolonged survival.
Conclusions:
- CD30 is a viable therapeutic target in eIMS, but BV efficacy is limited by resistance.
- Combination ALK and CD30-targeted therapy shows promise for treating eIMS, particularly at diagnosis.
- This combination strategy may be applicable to other CD30-positive, ALK-rearranged malignancies.
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