Author of

• 31609

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  P2.15 - Thymoma/Other Thoracic Malignancies (ID 185)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Thymoma/Other Thoracic Malignancies
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall

  • 31612

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    P2.15-03 - Tropomyosin-Related Kinase B Can Be a Biomarker of Prognosis and Therapeutic Target for Malignant Thymic Epithelial Tumors (ID 1274)

    10:15 - 18:15  |  Presenting Author(s): Keigo Ozono
    • Abstract

    Background
    

    Thymic epithelial tumors (TETs), mainly thymoma and thymic cancer are most common tumors arise in mediastinum. Histologically, thymoma is divided into Type A, AB, B1, B2 and B3. Clinically, TETs are divided into two groups, benign TETs (bTETs) as Type A, AB, B1 thymoma and malignant TETs (mTETs) as Type B2, B3 thymoma and thymic cancer.

    Complete surgical resection is vital for the management of TETs, and adjuvant therapy play important roles in the management of recurrent or metastasized cases. But there remains a lack of standard treatment after failure of adjuvant therapy. Development of molecular target therapies for advanced mTETs is a present issue.

    Tropomyosin receptor kinase (Trk) family is one of tyrosine kinase receptors consists of TrkA, TrkB and TrkC. Among them,TrkB have oncogenic factors in various cancers.

    Method
    

    Patients and case selection

    We analyzed 48 TETs (43 thymomas and 5 thymic cancers) patients who received curative surgical resection. We divided into two groups due to Masaoka-Koga stage (StageⅠ and Ⅱ as early stage and StageⅢ and Ⅳ as advanced).

    Immunohistochemistry

    Immunohistochemical staining was performed using tissue sections and primary antibodies, TrkA, TrkB and TrkC. We evaluated the immunoreactive cells by Allred score.

    Anchorage-dependent cell proliferation assay

    Proliferation assay was performed by using Trk inhibitor K252a, recombinant human BDNF (ligand of TrkB) and siRNA (Control-siRNA, TrkB-siRNA, and BDNF-siRNA).

    Result
    

    Trk expression in TETs.

    Early stage were 37 cases (77%) and advanced stage were 11 cases (22%). Benign TETs (bTETs) were 29 cases (60%) and malignant TETs (mTETs) were 19 cases (39%). The high expression of TrkA was observed in 5 cases (10%) and TrkB was 7 cases (14%). TrkC expression was not observed in 48 cases (0%). Among the TrkB-high, all the 5 thymic cancer cases indicated TrkB-high expression and remaining two cases were type B2 and type B3 thymoma. The TrkB-high type B2 thymoma was recurrent case.

    TrkB-high cases showed poor prognosis.

    Advanced showed significantly higher expression of TrkB than those with early cases (P<0.0001). TrkA and TrkC expression was no correlation with stage (TrkA: P=0.5163, TrkC:-). Cases with TrkB-high expression were significantly more in mTETs than in bTETs (P=0.0004). TrkA-high expression were no correlation with malignancy (P=0.9839).

    TrkB-high expression cases were significantly shorter overall survival periods (P=0.0482), compared to TrkB-low expression cases. There was no significant correlation between TrkA expression and survival periods (P=0.1484)

    The BDNF/TrkB signaling involve in proliferation ability of thymic cancer cell

    Tymic cancer cell, transfected with BDNF-siRNA or TrkB-siRNA showed significantly lower level of proliferation than with Control-siRNA, while administrating rhBDNF to the cell transfected with TrkB-siRNA showed no rising level of proliferation. These indicated knocking down of BDNF or TrkB suppressed proliferation.

    Cell incubated with rhBDNF showed significantly higher levels of proliferation than without rhBDNF. Administration of K252a and rhBDNF resulted in lower level of proliferation than without administration of K252a. These indicated proliferation was enhanced by rhBDNF and it was abrogated by Trk inhibitor K252a.

    Conclusion
    

    TrkB expression is a biomarker of prognosis and BDNF/TrkB signaling pathway can be a therapeutic target for mslignsnt thymic epithelial tumors.