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X. Li



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    MA 16 - Mediastinal, Tracheal and Esophageal Tumor: Multimodality Approaches (ID 675)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      MA 16.11 - Alterations of Notch Pathway among Patients with Adenoid Cystic Carcinoma of the Trachea and Its Impact on Survival (ID 9153)

      16:55 - 17:00  |  Author(s): X. Li

      • Abstract
      • Presentation
      • Slides

      Background:
      Adenoid cystic carcinoma (ACC) of the trachea represents less than 1% of all respiratory tract cancers and lacks well-characterized molecular markers. There is no standard of care treatment for patients with recurrent and/or metastatic disease. The aim of this study is to identify and characterize novel, activating mutations in Notch receptors in ACC of the trachea and to determine response to Notch inhibitor Brontictuzumab.

      Method:
      Patients with ACC of the trachea at four institutions from 2011 through 2016 were identified. Target exome sequencing or analysis of hotspot mutations in cancer-related genes was performed by next-generation sequencing. Luciferase reporter assays were performed to confirm target gene expression in vitro. Patient-derived xenograft (PDX) models were sequenced, and Notch-mutant models were treated with Brontictuzumab. Gene-expression and functional analyses were performed to study the mechanism of activation through mutation and inhibition by Brontictuzumab.

      Result:
      We showed that gain-of-function mutations of the Notch-1 gene in the PEST domain occurred in 10/62 tumors, leading to stabilization of the intracellular cleaved formed of Notch-1 (ICN1). Notch-1 mutations were associated with increased Notch-1 activation and its target gene HES-1. Mutations in Notch-2 (3/62), Notch-4 (3/62), Jagged-1 (2/62), FBXW-7 (4/62), and SPEN (1/62) were also identified in 13 (21.0%) patients. We observed a strong inverse correlation of mRNA levels between FBXW-7 and HES-1. Notch-1 mutations were associated with solid subtype (P = 0.02), advanced stage at diagnosis (P = 0.01), metastasis (P = 0.002), shorter relapse-free survival (RFS) (P = 0.008) and shorter overall survival (OS) (P = 0.006) compared with Notch-1 wild-type tumors. Notch-1 mutations were not an independent prognostic factor in the presence of histologic subtype and tumor stage. We demonstrated that Notch inhibition by Brontictuzumab reduced tumor cell proliferation and tumor formation in ACC patient-derived xenograft model harboring Notch-1 mutation.

      Conclusion:
      These data suggest that activated Notch pathway may be important to pathogenesis of ACC of the trachea and reveal Notch-1 as a target for therapeutic intervention in this subset of patients.

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