Modelling RANBP2-ALK-rearranged Epithelioid Inflammatory Myofibroblastic Sarcoma

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Copyright: Fordham, Ashleigh
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Abstract
Epithelioid inflammatory myofibroblastic sarcoma (eIMS) is an aggressive variant of inflammatory myofibroblastic tumour characterised by ALK staining that is perinuclear or cytoplasmic with perinuclear accentuation, CD30 expression and early relapse despite crizotinib treatment [1, 2]. This study aimed to generate and utilise models of eIMS to assess molecular-targeted therapeutic combinations to prevent and/or treat ALK inhibitor relapse. Two approaches were pursued to develop clinically relevant eIMS models. Malignant ascites from an eIMS patient at diagnosis and at relapse were used to establish cell and xenograft models. Patient-derived models were validated by confirmation of RANBP2-ALK rearrangement and expression of ALK and CD30. RANBP2-ALK transduced cell models did not recapitulate eIMS features despite expression of RANBP2-ALK at the RNA and protein levels. In vitro assays and in vivo dose response studies were undertaken to characterise the eIMS diagnosis and relapse models. Survival extension in the eIMS diagnosis xenografts compared to the relapse xenografts indicated the relapse model was less sensitive to ALK inhibition with crizotinib or ceritinib in vivo. However, this was not reflected by in vitro assays. Therefore, in vivo studies were used for the remainder of the project to validate novel therapeutic strategies identified in vitro. The CD30-targeted agent, brentuximab vedotin (BV) was investigated for therapeutic potential in eIMS. BV treatment resulted in tumour shrinkage in eIMS xenografts. However, reduced CD30 expression and induction of ABCB1 was associated with tumour regrowth during therapy. Therefore, combination therapies identified by rational selection and high-throughput screening were considered. BV resistance was reversed in vitro by combination with tariquidar, an ABCB1 inhibitor. The combination of rigosertib and BV, identified by high-throughput screening, was found to be synergistic in vitro. However, both these combinations only slowed growth of eIMS xenografts. In contrast, combining BV with crizotinib or ceritinib resulted in marked tumour shrinkage and improved survival in both eIMS diagnosis and relapse xenografts. This project established patient-derived in vitro and in vivo models of eIMS and identified therapeutic combinations for the treatment of eIMS. Prolonged tumour-free survival in vivo provides rationale to trial combinations of ALK inhibitors and BV for treatment of eIMS.
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Author(s)
Fordham, Ashleigh
Supervisor(s)
Trahair, Toby
MacKenzie, Karen
Fletcher, Jamie
Kavallaris, Maria
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Publication Year
2020
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
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