Abstract
BackgroundEpithelioid 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.MethodsMalignant ascites, from an eIMS patient at diagnosis and following multiple relapses, were used to generate matched diagnosis and relapse xenografts.ResultsXenografts 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.ConclusionsCD30 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.
Highlights
Epithelioid inflammatory myofibroblastic sarcoma is characterised by perinuclear anaplastic lymphoma kinase gene (ALK) localisation, CD30 expression and early relapse despite crizotinib treatment
Cell culture Epithelioid inflammatory myofibroblastic sarcoma (eIMS) cells were cultured from malignant ascites samples in flasks coated with 0.1% gelatine (Sigma-Aldrich) in Alpha minimum essential media (Invitrogen) plus 20% foetal bovine serum (FBS) (Life Technologies) in humidified incubators with 5% O2 and 5% CO2. eIMS samples were validated against patient germline DNA derived from peripheral blood by short tandem repeat (STR) profiling at the Garvan Institute for Medical Research or CellBank Australia (Table 1)
Establishment and validation of diagnosis and relapse patientderived eIMS xenografts eIMS cell cultures were established from malignant ascites collected from a patient at diagnosis and following multiple, sequential lines of treatment, including crizotinib, ceritinib and chemotherapy.[9,10]
Summary
Epithelioid inflammatory myofibroblastic sarcoma (eIMS) is characterised by perinuclear ALK localisation, CD30 expression and early relapse despite crizotinib treatment. Inflammatory myofibroblastic tumour (IMT) is a rare soft tissue sarcoma comprised of myofibroblastic spindle cells and an accompanying inflammatory infiltrate.[1,2,3,4,5] Chromosomal translocations resulting in fusion of the anaplastic lymphoma kinase gene (ALK) with a variety of partner genes occur in ~50% of IMTs.[6,7] RAN Binding Protein 2-ALK (RANBP2-ALK) rearranged epithelioid inflammatory myofibroblastic sarcoma (eIMS) is a clinically aggressive variant of IMT characterised by epithelioid tumour cell morphology, perinuclear ALK staining, CD30 expression and early relapse despite crizotinib treatment.[8,9,10] Additional therapeutic options are needed to prevent relapse and/or treat recurrent disease.
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