CD30 and ALK combination therapy has high therapeutic potency in RANBP2-ALK-rearranged epithelioid inflammatory myofibroblastic sarcoma.
Br J Cancer
; 123(7): 1101-1113, 2020 09.
Article
en En
| MEDLINE
| ID: mdl-32684628
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Sarcoma
/
Reordenamiento Génico
/
Antígeno Ki-1
/
Chaperonas Moleculares
/
Proteínas de Complejo Poro Nuclear
/
Miofibroblastos
/
Quinasa de Linfoma Anaplásico
Tipo de estudio:
Prognostic_studies
Límite:
Aged80
/
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Br J Cancer
Año:
2020
Tipo del documento:
Article
País de afiliación:
Australia
Pais de publicación:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
/
SCOTLAND
/
UK
/
UNITED KINGDOM