Unknown

Dataset Information

0

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


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.

SUBMITTER: Fordham AM 

PROVIDER: S-EPMC7524717 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC5337428 | biostudies-literature
| S-EPMC3014292 | biostudies-literature
| S-EPMC10952852 | biostudies-literature
| S-EPMC6263129 | biostudies-literature
| S-EPMC1850130 | biostudies-literature
| S-EPMC5045389 | biostudies-literature
| S-EPMC7142238 | biostudies-literature
| S-EPMC11336154 | biostudies-literature
| S-EPMC4770798 | biostudies-literature
| S-EPMC10158778 | biostudies-literature