Abstract A19: Establishment of in vitro and in vivo models of inflammatory myofibroblastic tumor

Abstract

Abstract Inflammatory myofibroblastic tumors (IMTs) are sarcomas of soft tissue that most commonly arise in children, adolescents, and young adults. If not cured by surgery, IMT has a high propensity for local recurrence as multifocal nodules, and may rapidly progress to fatal disease. Anaplastic Lymphoma Kinase (ALK) driven tumorigenesis is implicated in approximately 50% of IMT cases. IMT patients with ALK rearrangement have been reported to respond to the ALK inhibitor, crizotinib, but with the possibility of relapse with resistant disease. The second-generation ALK inhibitor ceritinib showed improved specificity and potency toward crizotinib-resistant tumors; however, resistant disease may still emerge. Thus, there is an urgent need for identifying alternative treatment options for ALK-driven IMT. In this study, we utilized fresh malignant ascites collected from a 9-year-old boy (IMT-1) with epithelioid inflammatory myofibroblastic sarcoma (eIMS), at diagnosis (IMT-1A) and third relapse (IMT-1D) to establish the in vitro cell culture and in vivo orthotopic patient-derived xenograft (PDX) model. Primary cell cultures were successfully established from both samples with confirmed ALK rearrangement. The PDX was established by intraperitoneal injection of cultured IMT-1D cells into nonobese diabetic severe combined immune-deficient mice with IL-2 receptor gamma chain deficiency (NSG) mice. Within 6-8 weeks of inoculation, 100% of the mice became moribund due to robust multifocal intraperitoneal tumors that grew in close association with abdominal organs, including the pancreas and small bowel. The xenograft recapitulated both morphologic and immunohistochemical features of the tumor within the patient. Positive immunohistochemical staining for ALK in a characteristic perinuclear membrane pattern and ALK gene rearrangement were also demonstrated in tumor cells cultured from peritoneal fluid of the xenografted mice. Our in vitro cultures and in vivo PDX models provide a valuable opportunity to undertake a detailed characterization of ALK-driven IMT at diagnosis and following ceritinib failure. They are ideal models for preclinical evaluation of new therapeutic approaches to the treatment of ALK-driven IMT. Citation Format: Jinhan (Angela) Xie, Emily V. A. Mould, Ashleigh Fordham, Andrew J. Gifford, Toby Trahair, Karen L. Mackenzie. Establishment of in vitro and in vivo models of inflammatory myofibroblastic tumor [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A19.